Advertisement

Applied Microbiology and Biotechnology

, Volume 102, Issue 21, pp 9037–9051 | Cite as

From nutraceutical to clinical trial: frontiers in Ganoderma development

  • Kai-Di Hsu
  • Kuan-Chen Cheng
Mini-Review

Abstract

Ganoderma spp. are medical mushrooms with various pharmacological compounds which are regarded as a nutraceutical for improving health and treating diseases. This review summarizes current progress in the studies of Gamoderma ranging from bioactive metabolites, bioactivities, production techniques to clinical trials. Traditionally, polysaccharides and ganoderic acids have been reported as the major bioactive metabolites of Ganoderma possessing anti-tumor and immunomodulation functions. Moreover, recent studies indicate that Gandoerma also exerts other bioactivities such as skin lighting, gut microbiota regulation, and anti-virus effects. However, since these medical fungi are rare in natural environment, and that the cost of cultivation of fruiting bodies is high, industrial submerged fermentation of Ganoderma mycelia promotes the development of Ganoderma by dint of an increase of biomass and bioactive metabolites used for further application. In addition, various strategies for production of different metabolites are well developed, such as gene regulation, bi-stage pH, and oxygen control. To date, Ganoderma not only has become one of the most popular nutraceuticals worldwide but also has been applied to clinical trials for advanced diseases such as breast and non-small-cell lung cancer.

Keywords

Ganoderma Nutraceutical Metabolites Clinical trials 

Notes

Acknowledgements

We would like to thank Yu-Hin Chan for revising this manuscript. This project was supported by the Ministry of Science and Technology, Taiwan (MOST 106-2628-E-002-009-MY3).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Akbar R, Yam WK (2011) Interaction of ganoderic acid on HIV related target: molecular docking studies. Bioinformation 7(8):413–417CrossRefGoogle Scholar
  2. Bhosle S, Ranadive K, Bapat G, Garad S, Deshpande G, Vaidya J (2010) Taxonomy and diversity of Ganoderma from the western parts of Maharashtra (India). Mycosphere 1(3):249–262Google Scholar
  3. Bishop KS, Kao CHJ, Xu YY, Glucina MP, Paterson RRM, Ferguson LR (2015) From 2000 years of Ganoderma lucidum to recent developments in nutraceuticals. Phytochemistry 114:56–65.  https://doi.org/10.1016/j.phytochem.2015.02.015 CrossRefPubMedGoogle Scholar
  4. Chan GCF, Chan WK, Sze DMY (2009) The effects of beta-glucan on human immune and cancer cells. J Hematol Oncol 2 doi:Artn 25 https://doi.org/10.1186/1756-8722-2-25
  5. Chang CJ, Lin CS, Lu CC, Martel J, Ko YF, Ojcius DM, Tseng SF, Wu TR, Chen YYM, Young JD, Lai HC (2015) Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota. Nat Commun 6:7489.  https://doi.org/10.1038/ncomms8489
  6. Chanmee T, Ontong P, Konno K, Itano N (2014) Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 6(3):1670–1690.  https://doi.org/10.3390/cancers6031670 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chen NH, Liu JW, Zhong JJ (2010) Ganoderic acid T inhibits tumor invasion in vitro and in vivo through inhibition of MMP expression. Pharmacol Rep 62(1):150–163CrossRefGoogle Scholar
  8. Chen SL, Xu J, Liu C, Zhu YJ, Nelson DR, Zhou SG, Li CF, Wang LZ, Guo X, Sun YZ, Luo HM, Li Y, Song JY, Henrissat B, Levasseur A, Qian J, Li JQ, Luo X, Shi LC, He L, Xiang L, Xu XL, Niu YY, Li QS, Han MV, Yan HX, Zhang J, Chen HM, Lv AP, Wang Z, Liu MZ, Schwartz DC, Sun C (2012a) Genome sequence of the model medicinal mushroom Ganoderma lucidum. Nat Commun 3:913.  https://doi.org/10.1038/ncomms1923 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chen Y, Bicker WF, Wu JY, Xie MY, Lindner WG (2012b) Simultaneous determination of 16 nucleosides and nucleobases by hydrophilic interaction chromatography and its application to the quality evaluation of Ganoderma. J Agr Food Chem 60(17):4243–4252.  https://doi.org/10.1021/jf300076j CrossRefGoogle Scholar
  10. Chen SY, Chang CL, Chen TH, Chang YW, Lin SB (2016) Colossolactone H, a new Ganoderma triterpenoid exhibits cytotoxicity and potentiates drug efficacy of gefitinib in lung cancer. Fitoterapia 114:81–91.  https://doi.org/10.1016/j.fitote.2016.08.015 CrossRefPubMedGoogle Scholar
  11. Chen SD, Li XM, Yong TQ, Wang ZG, Su JY, Jiao CW, Xie YZ, Yang BB (2017) Cytotoxic lanostane-type triterpenoids from the fruiting bodies of Ganoderma lucidum and their structure-activity relationships. Oncotarget 8(6):10071–10084.  https://doi.org/10.18632/oncotarget.14336
  12. Cheng S, Sliva D (2015) Ganoderma lucidum for cancer treatment: we are close but still not there. Integr Cancer Ther 14(3):249–257.  https://doi.org/10.1177/1534735414568721 CrossRefGoogle Scholar
  13. Chien CC, Tsai ML, Chen CC, Chang SJ, Tseng CH (2008) Effects on tyrosinase activity by the extracts of Ganoderma lucidum and related mushrooms. Mycopathologia 166(2):117–120.  https://doi.org/10.1007/s11046-008-9128-x CrossRefPubMedGoogle Scholar
  14. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NPJ, Lindegardh N, Socheat D, White NJ (2009) Artemisinin resistance in Plasmodium falciparum malaria. New Engl J Med 361(5):455–467.  https://doi.org/10.1056/NEJMoa0808859 CrossRefPubMedGoogle Scholar
  15. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin CC, Flavell RA (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13(11):759–771.  https://doi.org/10.1038/nrc3611 CrossRefPubMedGoogle Scholar
  16. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516.  https://doi.org/10.1080/01926230701320337 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Fang QH, Zhong JJ (2002a) Effect of initial pH on production of ganoderic acid and polysaccharide by submerged fermentation of Ganoderma lucidum. Process Biochem 37(7):769–774.  https://doi.org/10.1016/S0032-9592(01)00278-3 CrossRefGoogle Scholar
  18. Fang QH, Zhong JJ (2002b) Two-stage culture process for improved production of ganoderic acid by liquid fermentation of higher fungus Ganoderma lucidum. Biotechnol Prog 18(1):51–54.  https://doi.org/10.1021/Bp010136g CrossRefPubMedGoogle Scholar
  19. Fang QH, Tang YJ, Zhong JJ (2002) Significance of inoculation density control in production of polysaccharide and ganoderic acid by submerged culture of Ganoderma lucidum. Process Biochem 37(12):1375–1379.  https://doi.org/10.1016/S0032-9592(02)00017-1 CrossRefGoogle Scholar
  20. Fernando KMEP (2008) The host preference of a Ganoderma lucidum strain for three tree species of Fabaceae family; Cassia nodosa, Cassia fistula and Delonix regia. J Natl Sci Found Sri 36(4):323–326Google Scholar
  21. Ferreira ICFR, Heleno SA, Reis FS, Stojkovic D, Queiroz MJRP, Vasconcelos MH, Sokovic M (2015) Chemical features of Ganoderma polysaccharides with antioxidant, antitumor and antimicrobial activities. Phytochemistry 114:38–55.  https://doi.org/10.1016/j.phytochem.2014.10.011 CrossRefPubMedGoogle Scholar
  22. Flemming HC, Wingender J (2010) The biofilm matrix. Nat Rev Microbiol 8(9):623–633.  https://doi.org/10.1038/nrmicro2415 CrossRefPubMedGoogle Scholar
  23. Fraga I, Coutinho J, Bezerra RM, Dias AA, Marques G, Nunes FM (2014) Influence of culture medium growth variables on Ganoderma lucidum exopolysaccharides structural features. Carbohyd Polym 111:936–946.  https://doi.org/10.1016/j.carbpol.2014.05.047 CrossRefGoogle Scholar
  24. Gan KH, Fann YF, Hsu SH, Kuo KW, Lin CN (1998) Mediation of the cytotoxicity of lanostanoids and steroids of Ganoderma tsugae through apoptosis and cell cycle. J Nat Prod 61(4):485–487.  https://doi.org/10.1021/Np9704664 CrossRefGoogle Scholar
  25. Gao Y, Zhou S, Chen G, Dai X, Ye J (2002a) A phase I/II study of a Ganoderma lucidum (Curt.: Fr.) P. Karst. extract (Ganopofy) in patients with advanced cancer. Inter J Medic Mush 4(3):8.  https://doi.org/10.1615/IntJMedMushr.v4.i3.30 CrossRefGoogle Scholar
  26. Gao Y, Zhou S, Chen G, Dai X, Ye J, Gao H (2002b) A phase I/II study of a Ganoderma lucidum (Curt.: Fr.) P. Karst. (Ling Zhi, Reishi mushroom) extract in patients with chronic hepatitis. Inter J Medic Mush 4(4):7.  https://doi.org/10.1615/IntJMedMushr.v4.i4.50 CrossRefGoogle Scholar
  27. Gao Y, Dai X, Chen G, Ye J, Zhou S (2003a) A randomized, placebo-controlled, multicenter study of Ganoderma lucidum (W.Curt.:Fr.) Lloyd (Aphyllophoromycetideae) polysaccharides (Ganopoly) in patients with advanced lung cancer. Inter J Medic Mush 5(4):14.  https://doi.org/10.1615/InterJMedicMush.v5.i4.40 CrossRefGoogle Scholar
  28. Gao YH, Zhou SF, Jiang WQ, Huang M, Dai XH (2003b) Effects of Ganopoly (R) (a Ganoderma lucidum polysaccharide extract) on the immune functions in advanced-stage cancer patients. Immunol Investig 32(3):201–215.  https://doi.org/10.1081/Imm-120022979 CrossRefGoogle Scholar
  29. Gao Y, Lan J, Dai X, Ye J, Zhou S (2004) A phase I/II study of Ling Zhi mushroom Ganoderma lucidum (W.Curt.:Fr.) Lloyd (Aphyllophoromycetideae) extract in patients with type II diabetes mellitus. Inter J Medic Mush 6(1):8.  https://doi.org/10.1615/IntJMedMushr.v6.i1.30 CrossRefGoogle Scholar
  30. Gao JL, Leung KSY, Wang YT, Lai CM, Li SP, Hu LE, Lu GH, Jiang ZH, Yu ZL (2007) Qualitative and quantitative analyses of nucleosides and nucleobases in Ganoderma spp. by HPLC-DAD-MS. J Pharmaceut Biomed 44(3):807–811.  https://doi.org/10.1016/j.jpba.2007.03.012 CrossRefGoogle Scholar
  31. Gokce EC, Kahveci R, Atanur OM, Gurer B, Aksoy N, Gokce A, Sargon MF, Cemil B, Erdogan B, Kahveci O (2015) Neuroprotective effects of Ganoderma lucidum polysaccharides against traumatic spinal cord injury in rats. Injury 46(11):2146–2155.  https://doi.org/10.1016/j.injury.2015.08.017 CrossRefPubMedGoogle Scholar
  32. Hajjaj H, Mace C, Roberts M, Niederberger P, Fay LB (2005) Effect of 26-oxygenosterols from Ganoderma lucidum and their activity as cholesterol synthesis inhibitors. Appl Environ Microb 71(7):3653-3658.  https://doi.org/10.1128/Aem.71.7.3653-3658.2005 CrossRefGoogle Scholar
  33. Hamdan D, Leboeuf C, Pereira C, Jourdan N, Verneuil L, Bousquet G, Janin A (2015) A digestive allergic reaction with hypereosinophilia imputable to docetaxel in a breast cancer patient: a case report. BMC Cancer 15:993.  https://doi.org/10.1186/s12885-015-2008-0 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hashim SNNS, Schwarz LJ, Danylec B, Mitri K, Yang YZ, Boysen RI, Hearn MTW (2016) Recovery of ergosterol from the medicinal mushroom, Ganoderma tsugae var. Janniae, with a molecularly imprinted polymer derived from a cleavable monomer-template composite. J Chromatogr A 1468:1–9.  https://doi.org/10.1016/j.chroma.2016.09.004 CrossRefGoogle Scholar
  35. Hsin IL, Ou CC, Wu MF, Jan MS, Hsiao YM, Lin CH, Ko JL (2015) GMI, an immunomodulatory protein from Ganoderma microsporum, potentiates cisplatin-induced apoptosis via autophagy in lung cancer cells. Mol Pharm 12(5):1534–1543.  https://doi.org/10.1021/mp500840z CrossRefPubMedGoogle Scholar
  36. Hsu KD, Chen HJ, Wang CS, Lum CC, Wu SP, Lin SP, Cheng KC (2016) Extract of Ganoderma formosanum mycelium as a highly potent tyrosinase inhibitor. Sci Rep-Uk 6:32854.  https://doi.org/10.1038/srep CrossRefGoogle Scholar
  37. Hsu KD, Wu SP, Lin SP, Lum CC, Cheng KC (2017) Enhanced active extracellular polysaccharide production from Ganoderma formosanum using computational modeling. J Food Drug Anal 25(4):804–811.  https://doi.org/10.1016/j.jfda.2016.12.006 CrossRefPubMedGoogle Scholar
  38. Hsu KD, Chan YH, Chen HJ, Lin SP, Cheng KC (2018) Tyrosinase-based TLC autography for anti-melanogenic drug screening. Sci Rep 8(1):401.  https://doi.org/10.1038/s41598-017-18720-0 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Huang L, Sun F, Liang CY, He YX, Bao R, Liu LX, Zhou CZ (2009) Crystal structure of LZ-8 from the medicinal fungus Ganoderma lucidium. Proteins 75(2):524–527.  https://doi.org/10.1002/prot.22346 CrossRefPubMedGoogle Scholar
  40. Huang SC, Mao JX, Ding K, Zhou Y, Zeng XL, Yang WJ, Wang PP, Zhao C, Yao J, Xia P, Pei G (2017) Polysaccharides from Ganoderma lucidum promote cognitive function and neural progenitor proliferation in mouse model of Alzheimer's disease. Stem Cell Rep 8(1):84–94.  https://doi.org/10.1016/j.stemcr.2016.12.007 CrossRefGoogle Scholar
  41. Kang D, Mutakin M, Levita J (2015) Computational study of triterpenoids of Ganoderma lucidum with aspartic protease enzymes for discovering HIV-1 and plasmepsin inhibitors. Int J Chem 2015:7(1).  https://doi.org/10.5539/ijc.v7n1p62 CrossRefGoogle Scholar
  42. Kawagishi H, Fukuhara F, Sazuka M, Kawashima A, Mitsubori T, Tomita T (1993) 5'-Deoxy-5'-methylsulphinyladenosine, a platelet-aggregation inhibitor from Ganoderma lucidum. Phytochemistry 32(2):239–241.  https://doi.org/10.1016/S0031-9422(00)94974-4 CrossRefGoogle Scholar
  43. Kino K, Yamashita A, Yamaoka K, Watanabe J, Tanaka S, Ko K, Shimizu K, Tsunoo H (1989) Isolation and characterization of a new immunomodulatory protein, Ling Zhi-8 (Lz-8), from Ganoderma lucidium. J Biol Chem 264(1):472–478PubMedGoogle Scholar
  44. Klupp NL, Kiat H, Bensoussan A, Steiner GZ, Chang DH (2016) A double-blind, randomised, placebo-controlled trial of Ganoderma lucidum for the treatment of cardiovascular risk factors of metabolic syndrome. Sci Rep-Uk 6:29540.  https://doi.org/10.1038/srep29540
  45. Lakornwong W, Kanokmedhakul K, Kanokmedhakul S, Kongsaeree P, Prabpai S, Sibounnavong P, Soytong K (2014) Triterpene lactones from cultures of Ganoderma sp. KM01. J Nat Prod 77(7):1545–1553.  https://doi.org/10.1021/np400846k CrossRefPubMedGoogle Scholar
  46. Lee KM, Lee SY, Lee HY (1999) Bistage control of pH for improving exopolysaccharide production from mycelia of Ganoderma lucidum in an air-lift fermentor. J Biosci Bioeng 88(6):646–650.  https://doi.org/10.1016/S1389-1723(00)87094-2 CrossRefPubMedGoogle Scholar
  47. Lee WY, Park Y, Ahn JK, Ka KH, Park SY (2007) Factors influencing the production of endopolysaccharide and exopolysaccharide from Ganoderma applanatum. Enzyme Microb Tech 40(2):249–254.  https://doi.org/10.1016/j.enzmictec.2006.04.009 CrossRefGoogle Scholar
  48. Levita J, Chao KH, Mutakin (2014) Interactions of ganoderiol-F with aspartic proteases of HIV and plasmepsin for anti-HIV and anti-malarial discovery. Int J Pharm Pharm Sci 6(5):561–566Google Scholar
  49. Li EK, Tam LS, Wong CK, Li WC, Lam CWK, Wachtel-Galor S, Benzie IFF, Bao YX, Leung PC, Tomlinson B (2007) Safety and efficacy of Ganoderma lucidum (Lingzhi) and San miao San supplementation in patients with rheumatoid arthritis: a double-blind, randomized, placebo-controlled pilot trial. Arthrit Rheum-Arthr 57(7):1143–1150.  https://doi.org/10.1002/art.22994 CrossRefGoogle Scholar
  50. Li JQ, Zhang JH, Chen HM, Chen XD, Lan J, Liu C (2013) Complete mitochondrial genome of the medicinal mushroom Ganoderma lucidum. Plos One 8(8):e72038.  https://doi.org/10.1371/journal.pone.0072038 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Li JR, Cheng CL, Yang WJ, Yang CR, Ou YC, Wu MJ, Ko JL (2014) FIP-gts potentiate autophagic cell death against cisplatin-resistant urothelial cancer cells. Anticancer Res 34(6):2973–2983PubMedGoogle Scholar
  52. Li AM, Shuai XY, Jia ZJ, Li HY, Liang XB, Su DM, Guo WH (2015) Ganoderma lucidum polysaccharide extract inhibits hepatocellular carcinoma growth by downregulating regulatory T cells accumulation and function by inducing microRNA-125b. J Transl Med 13:100.  https://doi.org/10.1186/s12967-015-0465-5 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Liao SF, Liang CH, Ho MY, Hsu TL, Tsai TI, Hsieh YSY, Tsai CM, Li ST, Cheng YY, Tsao SM, Lin TY, Lin ZY, Yang WB, Ren CT, Lin KI, Khoo KH, Lin CH, Hsu HY, Wu CY, Wong CH (2013) Immunization of fucose-containing polysaccharides from Reishi mushroom induces antibodies to tumor-associated Globo H-series epitopes. P Natl Acad Sci USA 110(34):13809–13814.  https://doi.org/10.1073/pnas.1312457110 CrossRefGoogle Scholar
  54. Lin TY, Hsu HY (2016) Ling Zhi-8 reduces lung cancer mobility and metastasis through disruption of focal adhesion and induction of MDM2-mediated Slug degradation. Cancer Lett 375(2):340–348.  https://doi.org/10.1016/j.canlet.2016.03.018 CrossRefPubMedGoogle Scholar
  55. Lin CC, Yu YL, Shih CC, Liu KJ, Ou KL, Hong LZ, Chen JDC, Chu CL (2011) A novel adjuvant Ling Zhi-8 enhances the efficacy of DNA cancer vaccine by activating dendritic cells. Cancer Immunol Immun 60(7):1019–1027.  https://doi.org/10.1007/s00262-011-1016-4 CrossRefGoogle Scholar
  56. Liu J, Shimizu K, Konishi F, Kumamoto S, Kondo R (2007) The anti-androgen effect of ganoderol B isolated from the fruiting body of Ganoderma lucidum. Bioorgan Med Chem 15(14):4966–4972.  https://doi.org/10.1016/j.bmc.2007.04.036 CrossRefGoogle Scholar
  57. Liu J, Shiono J, Shimizu K, Kukita A, Kukita T, Kondo R (2009) Ganoderic acid DM: anti-androgenic osteoclastogenesis inhibitor. Bioorg Med Chem Lett 19(8):2154–2157.  https://doi.org/10.1016/j.bmcl.2009.02.119 CrossRefPubMedGoogle Scholar
  58. Liu CD, Dunkin D, Lai J, Song Y, Ceballos C, Benkov K, Li XM (2015a) Anti-inflammatory effects of Ganoderma lucidum triterpenoid in human Crohn’s disease associated with downregulation of NF-kappa B signaling. Inflamm Bowel Dis 21(8):1918–1925.  https://doi.org/10.1097/Mib.0000000000000439 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Liu CD, Yang N, Song Y, Wang LX, Zi JC, Zhang SW, Dunkin D, Busse P, Weir D, Tversky J, Miller RL, Goldfarb J, Zhan JX, Li XM (2015b) Ganoderic acid C-1 isolated from the anti-asthma formula, ASHMI (TM) suppresses TNF-alpha production by mouse macrophages and peripheral blood mononuclear cells from asthma patients. Int Immunopharmacol 27(2):224–231.  https://doi.org/10.1016/j.intimp.2015.05.018 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Madeo F, Herker E, Wissing S, Jungwirth H, Eisenberg T, Frohlich KU (2004) Apoptosis in yeast. Curr Opin Microbiol 7(6):655–660.  https://doi.org/10.1016/j.mib.2004.10.012 CrossRefPubMedGoogle Scholar
  61. Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:13.  https://doi.org/10.12703/P6-13 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Meng LZ, Xie J, Lv GP, Hu DJ, Zhao J, Duan JA, Li SP (2014) A comparative study on immunomodulatory activity of polysaccharides from two official species of Ganoderma (Lingzhi). Nutr Cancer 66(7):1124–1131.  https://doi.org/10.1080/01635581.2014.948215 CrossRefPubMedGoogle Scholar
  63. Mukaiyama T, Tsujimura N, Otaka S, Kosaka Y, Hata K, Hori K, Sakamoto K (2009) Anti-melanogenic activity of ergosterol peroxide from Ganoderma lucidum on a mouse melanoma cell line. In: Shirahata S, Ikura K, Nagao M, Ichikawa A, Teruya K (eds) Animal cell technology: basic & applied aspects. Animal cell technology: basic & applied aspects, vol 15. Springer, Dordrecht, pp 273–277CrossRefGoogle Scholar
  64. Ou CC, Hsiao YM, Hou TY, Wu MF, Ko JL (2015) Fungal immunomodulatory proteins alleviate docetaxel-induced adverse effects. J Funct Foods 19:451–463.  https://doi.org/10.1016/j.jff.2015.09.042 CrossRefGoogle Scholar
  65. Papinutti L (2010) Effects of nutrients, pH and water potential on exopolysaccharides production by a fungal strain belonging to Ganoderma lucidum complex. Bioresour Technol 101(6):1941–1946.  https://doi.org/10.1016/j.biortech.2009.09.076 CrossRefPubMedGoogle Scholar
  66. Postemsky PD, Bidegain MA, Gonzalez-Matute R, Figlas ND, Cubitto MA (2017) Pilot-scale bioconversion of rice and sunflower agro-residues into medicinal mushrooms and laccase enzymes through solid-state fermentation with Ganoderma lucidum. Bioresour Technol 231:85–93.  https://doi.org/10.1016/j.biortech.2017.01.064 CrossRefPubMedGoogle Scholar
  67. Russell R, Paterson M (2006) Ganoderma—a therapeutic fungal biofactory. Phytochemistry 67(18):1985–2001.  https://doi.org/10.1016/j.phytochem.2006.07.004 CrossRefGoogle Scholar
  68. Shi LA, Ren A, Mu DS, Zhao MW (2010) Current progress in the study on biosynthesis and regulation of ganoderic acids. Appl Microbiol Biot 88(6):1243–1251.  https://doi.org/10.1007/s00253-010-2871-1 CrossRefGoogle Scholar
  69. Shimizu A, Yano T, Saito Y, Inada Y (1985) Isolation of an inhibitor of platelet-aggregation from a fungus, Ganoderma lucidum. Chem Pharm Bull 33(7):3012–3015CrossRefGoogle Scholar
  70. Straub KL, Benz M, Schink B (2001) Iron metabolism in anoxic environments at near neutral pH. FEMS Microbiol Ecol 34(3):181–186.  https://doi.org/10.1111/j.1574-6941.2001.tb00768.x CrossRefPubMedGoogle Scholar
  71. Sun LX, Lin ZB, Lu J, Li WD, Niu YD, Sun Y, Hu CY, Zhang GQ, Duan XS (2017) The improvement of M1 polarization in macrophages by glycopeptide derived from Ganoderma lucidum. Immunol Res 65(3):658–665.  https://doi.org/10.1007/s12026-017-8893-3 CrossRefPubMedGoogle Scholar
  72. Tan NZ, Gao L, Xu C, Yang JY, Zhang Y, Zhao CS, Dong YZ, Lu JH, Han J, Zhu JS (2014) Ganoderma lucidum ReishiMax restored aging-related changes in expressions of multiple gene pathways in normal aging mice. FASEB J 28(1)Google Scholar
  73. Tanaka S, Ko K, Kino K, Tsuchiya K, Yamashita A, Murasugi A, Sakuma S, Tsunoo H (1989) Complete amino acid sequence of an immunomodulatory protein, Ling Zhi-8 (Lz-8) an immunomodulator from a fungus, Ganoderma lucidium, having similarity to immunoglobulin variable regions. J Biol Chem 264(28):16372–16377PubMedGoogle Scholar
  74. Tang YJ, Zhong JJ (2003) Role of oxygen supply in submerged fermentation of Ganoderma lucidum for production of Ganoderma polysaccharide and ganoderic acid. Enzyme Microb Tech 32(3–4):478–484.  https://doi.org/10.1016/S0141-0229(02)00338-1 CrossRefGoogle Scholar
  75. Tang YJ, Zhang W, Zhong JJ (2009) Performance analyses of a pH-shift and DOT-shift integrated fed-batch fermentation process for the production of ganoderic acid and Ganoderma polysaccharides by medicinal mushroom Ganoderma lucidum. Bioresour Technol 100(5):1852–1859.  https://doi.org/10.1016/j.biortech.2008.10.005 CrossRefPubMedGoogle Scholar
  76. Tang YJ, Zhang W, Liu RS, Zhu LW, Zhong JJ (2011) Scale-up study on the fed-batch fermentation of Ganoderma lucidum for the hyperproduction of ganoderic acid and Ganoderma polysaccharides. Process Biochem 46(1):404–408.  https://doi.org/10.1016/j.procbio.2010.08.013 CrossRefGoogle Scholar
  77. Tao J, Feng KY (1990) Experimental and clinical studies on inhibitory effect of ganoderma lucidum on platelet aggregation. J Tongji Med Univ 10(4):240–243CrossRefGoogle Scholar
  78. Wang HQ, Zhong JJ, Yu JT (1997) Enhanced production of taxol in suspension cultures of Taxus chinensis by controlling inoculum size. Biotechnol Lett 19(4):353–355.  https://doi.org/10.1023/A:1018355002041 CrossRefGoogle Scholar
  79. Wang XM, Yang M, Guan SH, Liu RX, Xia JM, Bi KS, Guo DA (2006) Quantitative determination of six major triterpenoids in Ganoderma lucidum and related species by high performance liquid chromatography. J Pharmaceut Biomed 41(3):838–844.  https://doi.org/10.1016/j.jpba.2006.01.053 CrossRefGoogle Scholar
  80. Wang CL, Pi CC, Kuo CW, Zhuang YJ, Khoo KH, Liu WH, Chen CJ (2011) Polysaccharides purified from the submerged culture of Ganoderma formosanum stimulate macrophage activation and protect mice against Listeria monocytogenes infection. Biotechnol Lett 33(11):2271–2278.  https://doi.org/10.1007/s10529-011-0697-2 CrossRefPubMedGoogle Scholar
  81. Wang CL, Lu CY, Pi CC, Zhuang YJ, Chu CL, Liu WH, Chen CJ (2012) Extracellular polysaccharides produced by Ganoderma formosanum stimulate macrophage activation via multiple pattern-recognition receptors. Bmc Complem Altern M 12 doi:Artn 119  https://doi.org/10.1186/1472-6882-12-119
  82. Wang CL, Lu CY, Hsueh YC, Liu WH, Chen CJ (2014a) Activation of antitumor immune responses by Ganoderma formosanum polysaccharides in tumor-bearing mice. Appl Microbiol Biot 98(22):9389–9398.  https://doi.org/10.1007/s00253-014-6027-6 CrossRefGoogle Scholar
  83. Wang JG, Yuan YH, Yue TL (2014b) Immunostimulatory activities of beta-D-glucan from Ganoderma lucidum. Carbohyd Polym 102:47–54.  https://doi.org/10.1016/j.carbpol.2013.10.087 CrossRefGoogle Scholar
  84. Wang N, Liang HW, Zen K (2014c) Molecular mechanisms that influence the macrophage M1-M2 polarization balance. Front Immunol 5 doi:ARTN 614 https://doi.org/10.3389/fimmu.2014.00614
  85. Wei ZH, Duan YY, Qian YQ, Guo XF, Li YJ, Jin SH, Zhou ZX, Shan SY, Wang CR, Chen XJ, Zheng YG, Zhong JJ (2014) Screening of Ganoderma strains with high polysaccharides and ganoderic acid contents and optimization of the fermentation medium by statistical methods. Bioprocess Biosyst Eng 37(9):1789–1797.  https://doi.org/10.1007/s00449-014-1152-2 CrossRefPubMedGoogle Scholar
  86. Weng YF, Xiang L, Matsuura A, Zhang Y, Huang QM, Qi JH (2010) Ganodermasides A and B, two novel anti-aging ergosterols from spores of a medicinal mushroom Ganoderma lucidum on yeast via UTH1 gene. Bioorgan Med Chem 18(3):999–1002.  https://doi.org/10.1016/j.bmc.2009.12.070 CrossRefGoogle Scholar
  87. Weng YF, Lu J, Xiang L, Matsuura A, Zhang Y, Huang QM, Qi JH (2011) Ganodermasides C and D, two new anti-aging ergosterols from spores of the medicinal mushroom Ganoderma lucidum. Biosci Biotechnol Biochem 75(4):800–803.  https://doi.org/10.1271/bbb.100918 CrossRefPubMedGoogle Scholar
  88. Wu QP, Xie YZ, Deng ZQ, Li XM, Yang WN, Jiao CW, Fang L, Li SZ, Pan HH, Yee AJ, Lee DY, Li C, Zhang Z, Guo J, Yang BB (2012) Ergosterol peroxide isolated from Ganoderma lucidum abolishes microRNA miR-378-mediated tumor cells on chemoresistance. Plos One 7(8):e44579.  https://doi.org/10.1371/journal.pone.0044579 CrossRefPubMedPubMedCentralGoogle Scholar
  89. Wu GS, Guo JJ, Bao JL, Li XW, Chen XP, Lu JJ, Wang YT (2013) Anti-cancer properties of triterpenoids isolated from Ganoderma lucidum—a review. Expert Opin Inv Drug 22(8):981–992.  https://doi.org/10.1517/13543784.2013.805202 CrossRefGoogle Scholar
  90. Xu JW, Xu YN, Zhong JJ (2010) Production of individual ganoderic acids and expression of biosynthetic genes in liquid static and shaking cultures of Ganoderma lucidum. Appl Microbiol Biot 85(4):941–948.  https://doi.org/10.1007/s00253-009-2106-5 CrossRefGoogle Scholar
  91. Xu JW, Ji SL, Li HJ, Zhou JS, Duan YQ, Dang LZ, Mo MH (2015) Increased polysaccharide production and biosynthetic gene expressions in a submerged culture of Ganoderma lucidum by the overexpression of the homologous alpha-phosphoglucomutase gene. Bioprocess Biosyst Eng 38(2):399–405.  https://doi.org/10.1007/s00449-014-1279-1 CrossRefPubMedGoogle Scholar
  92. Xue Q, Ding YX, Shang CH, Jiang C, Zhao MW (2008) Functional expression of LZ-8, a fungal immunomodulatory protein from Ganoderma lucidium in Pichia pastoris. J Gen Appl Microbiol 54(6):393–398CrossRefGoogle Scholar
  93. Yeh CH, Chen HC, Yang JJ, Chuang WI, Sheu F (2010) Polysaccharides PS-G and protein LZ-8 from Reishi (Ganoderma lucidum) exhibit diverse functions in regulating murine macrophages and T lymphocytes. J Agr Food Chem 58(15):8535–8544.  https://doi.org/10.1021/jf100914m CrossRefGoogle Scholar
  94. You BJ, Lee MH, Tien N, Lee MS, Hsieh HC, Tseng LH, Chung YL, Lee HZ (2013) A novel approach to enhancing ganoderic acid production by Ganoderma lucidum using apoptosis induction. Plos One 8(1):e53616.  https://doi.org/10.1371/journal.pone.0053616 CrossRefPubMedPubMedCentralGoogle Scholar
  95. You BJ, Tien N, Lee MH, Bao BY, Wu YS, Hu TC, Lee HZ (2017) Induction of apoptosis and ganoderic acid biosynthesis by cAMP signaling in Ganoderma lucidum. Sci Rep-Uk 7:318.  https://doi.org/10.1038/s41598-017-00281-x CrossRefGoogle Scholar
  96. Yue QX, Song XY, Ma C, Feng LX, Guan SH, Wu WY, Yang M, Jiang BH, Liu X, Cui YJ, Guo DA (2010) Effects of triterpenes from Ganoderma lucidum on protein expression profile of HeLa cells. Phytomedicine 17(8–9):606–613.  https://doi.org/10.1016/j.phymed.2009.12.013 CrossRefPubMedGoogle Scholar
  97. Yuen JWM, Gohel MDI (2005) Anticancer effects of Ganoderma lucidum: a review of scientific evidence. Nutr Cancer 53(1):11–17.  https://doi.org/10.1207/s15327914nc5301_2 CrossRefPubMedGoogle Scholar
  98. Zhang WX, Zhong JJ (2013) Oxygen limitation improves ganoderic acid biosynthesis in submerged cultivation of Ganoderma lucidum. Biotechnol Bioproc E 18(5):972–980.  https://doi.org/10.1007/s12257-013-0148-0 CrossRefGoogle Scholar
  99. Zhang L, Ding ZY, Xu P, Wang YH, Gu ZH, Qian Z, Shi GY, Zhang KC (2011) Methyl lucidenate F isolated from the ethanol-soluble-acidic components of Ganoderma lucidum is a novel tyrosinase inhibitor. Biotechnol Bioproc E 16(3):457–461.  https://doi.org/10.1007/s12257-010-0345-z CrossRefGoogle Scholar
  100. Zhang N, Yin Y, Xu SJ, Wu YP, Chen WS (2012) Inflammation & apoptosis in spinal cord injury. Indian J Med Res 135(3):287–296PubMedPubMedCentralGoogle Scholar
  101. Zhang SS, Nie SP, Huang DF, Feng YL, Xie MY (2014a) A novel polysaccharide from Ganoderma atrum exerts antitumor activity by activating mitochondria-mediated apoptotic pathway and boosting the immune system. J Agr Food Chem 62(7):1581–1589.  https://doi.org/10.1021/jf4053012 CrossRefGoogle Scholar
  102. Zhang WJ, Tao JY, Yang XP, Yang ZL, Zhang L, Liu HS, Wu KL, Wu JG (2014b) Antiviral effects of two Ganoderma lucidum triterpenoids against enterovirus 71 infection. Biochem Bioph Res Co 449(3):307–312.  https://doi.org/10.1016/j.bbrc.2014.05.019 CrossRefGoogle Scholar
  103. Zhao W, Xu JW, Zhong JJ (2011) Enhanced production of ganoderic acids in static liquid culture of Ganoderma lucidum under nitrogen-limiting conditions. Bioresour Technol 102(17):8185–8190.  https://doi.org/10.1016/j.biortech.2011.06.043 CrossRefPubMedGoogle Scholar
  104. Zhou S, Gao Y, Chan E (2005) Clinical trials for medicinal mushrooms: experience with Ganoderma lucidum (W.Curt.:Fr.) Lloyd (Lingzhi mushroom). Inter J Medic Mush 7(1&2):111–118.  https://doi.org/10.1615/IntJMedMushr.v7.i12.110 CrossRefGoogle Scholar
  105. Zhou JS, Ji SL, Ren MF, He YL, Jing XR, Xu JW (2014) Enhanced accumulation of individual ganoderic acids in a submerged culture of Ganoderma lucidum by the overexpression of squalene synthase gene. Biochem Eng J 90:178–183.  https://doi.org/10.1016/j.bej.2014.06.008 CrossRefGoogle Scholar
  106. Zhu QC, Bang TH, Ohnuki K, Sawai T, Sawai K, Shimizu K (2015) Inhibition of neuraminidase by Ganoderma triterpenoids and implications for neuraminidase inhibitor design. Sci Rep-Uk 5 doi:ARTN 13194 https://doi.org/10.1038/srep13194, 5
  107. Zou X, Sun M, Guo X (2006) Quantitative response of cell growth and polysaccharide biosynthesis by the medicinal mushroom Phellinus linteus to NaCl in the medium. World J Microb Biot 22(11):1129–1133.  https://doi.org/10.1007/s11274-006-9153-1 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of BiotechnologyNational Taiwan UniversityTaipeiTaiwan
  2. 2.Graduate Institute of Food Science TechnologyNational Taiwan UniversityTaipeiTaiwan
  3. 3.Department of Medical Research, China Medical University HospitalChina Medical UniversityTaipeiTaiwan

Personalised recommendations