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Ganoderma lucidum (Reishi, Lingzhi)

A series of trials evaluating Ganoderma lucidum in several disease states have been carried out. The trials evaluated effects on cancer, type 2 diabetes, coronary heart disease, chronic hepatitis B, and neurasthenia. Treatment with Ganopoly for 12 weeks showed hypoglycemic activity and produced some anti-viral and liver protective effects in patients with chronic hepatitis B infection. However, the same treatment regimen did not result in any objective response in late-stage cancer patients (Zhou et al., 2005). Overall, the findings suggest that Ganopoly may have some pharmacological activities, although clinical proof is lacking.

The efficacy and safety of Senseiro (containing extracts from Agaricus blazei Murill) and Rokkaku Reishi, (containing the Ganoderma lucidum mushroom) have been evaluated over 6 months in patients with prostate cancer in Japan (Yoshimura et al., 2010). Patients with biochemical failure after radical treatment for non-metastasized prostate cancer were enrolled in this open-label study. No partial response in terms of serum prostate-specific antigen was observed. Alteration of serum prostate-specific antigen doubling time did not correlate with that of serum testosterone levels.

Ganoderma lucidum

Serious adverse effects were not observed and no significant anticancer effects were observed with the intake of these two mushrooms in the study population.

A double-blind, placebo-controlled, randomized, and dose-ranging study has been carried out in men with lower urinary tract symptoms (LUTS) to evaluate the safety and efficacy of an extract of Ganoderma lucidum that shows the strongest 5-alpha-reductase inhibitory activity among the extracts of 19 edible and medicinal mushrooms. In this trial, 88 men over the age of 49 years who had slight-to-moderate LUTS were randomly assigned to 12 weeks of treatment with G. lucidum extract (6mg once per day) or placebo. The primary outcome measures were changes in the International Prostate Symptom Score (IPSS) and variables of uroflowmetry. Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, laboratory values, and the reported adverse effects. G. lucidum was effective and significantly superior to placebo for improving total IPSS with 2.1 points decreasing at the end of treatment. No changes were observed with respect to quality of life scores, peak urinary flow, mean urinary flow, residual urine, prostate volume, serum prostate-specific antigen, or testosterone levels. Overall treatment was well tolerated with no severe adverse effects (Noguchi et al., 2008a).

Ganoderma lucidum (Reishi, Lingzhi) has been reported to suppress the invasive behaviour of breast cancer cells by inhibiting the transcription factor NF-kappaB and to inhibit the growth of MDA-MB-231 breast cancer cells by modulating Akt/NF-kappaB signaling (Jiang et al., 2004a).

A subsequent study by the same group on the proliferation of human estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) breast cancer cells has reported that G. lucidum inhibits proliferation of human breast cancer cells and contains biologically active compounds with specificity against the estrogen receptor and NF-kappaB (transcription factor) signalling (Jiang et al., 2006).

Aqueous extracts of fruiting bodies of Ganoderma lucidum, G. sinense, and G. tsugae have been reported to have anti-tumour activities in human breast cancer cells and immunomodulatory activities in murine lymphocytes. In addition, it has also been suggested that the stipes of fruiting bodies of Ganoderma species should be included in the preparation of extracts of these fungi in order to obtain the most comprehensive active ingredients (Yue et al., 2006). An extract of Ganoderma lucidum has also been reported to reduce chemically-induced mammary adenocarcinomas in Sprague Dawley rats (Lakshmi et al., 2009).

The effect of G. lucidum on oxidative stress-induced metastatic behaviour of poorly-invasive MCF­7 breast cancer cells has also been studied and it has been shown that G. lucidum inhibited oxidative stress-induced migration of MCF-7 cells by the down-regulation of mitogen activated protein kinase (MAPK) signalling, which is involved in hormonal signalling cascades. G. lucidum suppressed oxidative stress stimulated phosphorylation of extracellular signal-regulated protein kinases (Erk1/2), which resulted in the down-regulation of expression of c-fos, and in the inhibition of transcription factors AP-1 and NF-kappaB. The biological effect of G. lucidum on cell migration was mediated by the suppression of secretion of interleukin-8 from MCF-7 cells exposed to oxidative stress. These results suggest that G. lucidum inhibited the oxidative stress-induced invasive behaviour of breast cancer cells by modulating Erk1/2 signalling and could possibly be considered as an antioxidant in adjuvant cancer therapy (Thyagarajan et al., 2006).

A further study by the same group has also shown that an extract from green tea (GTE) increased the anti-cancer effect of G. lucidum extract (GLE) on cell proliferation (anchorage-dependent growth) as well as colony formation (anchorage-independent growth) of breast cancer cells. The effect was mediated by the down-regulation of expression of the oncogene c-myc in MDA-MB-231 cells. Although individual GTE and GLE independently inhibited adhesion, migration and invasion of MDA-MB-231 cells, their combination demonstrated a synergistic effect, which was mediated by the suppression of secretion of urokinase plasminogen activator (uPA) from breast cancer cells suggesting a potential use of combined green tea and G. lucidum extracts for the suppression of growth and invasiveness of metastatic breast cancers (Thyagarajan et al., 2007).

A protein from Ganoderma lucidum has also been shown to effectively promote the activation and maturation of immature human monocyte-derived dendritic cells, preferring a Th1 response, suggesting that the protein may possess a potential effect in regulating immune responses (Lin et al., 2009b). These immunomodulatory effects were shown to be mediated via NF-kappaB and Mitogen Activated Protein Kinase (MAPK) pathways.

The effects of Ganoderma lucidum (Basidiomycetes) polysaccharide (GL-PS) extract on tumour volume and T(CD4+/CD8+) ratio of tumour infiltrating lymphocytes (TILs) in breast cancer bearing mice have been studied. The results indicated that GL-PS (100mg/kg/day) could effectively increase the delayed type hypersensitivity response against sRBC in BALB/c mice. Furthermore, intraperitoneal injection of this extract in breast cancer bearing mice could increase T-cell infiltration into the tumour. The authors concluded that GL-PS can exhibit a potent immunomodulatory effect and may be used for potentiation of the immune system against diseases such as cancer and other conditions in which the immune response has been compromised (Mojadadi et al., 2006).

An alcohol extract from the spore of Ganoderma lucidum has also been shown to inhibit the in vitro proliferation of human umbilical vein endothelial cells and MDA-MB-231 human breast cancer cells. Further fractionation of the alcohol extract revealed that the ethyl acetate fraction inhibited both cell lines in a dose-dependent manner from 2 to 40µg/ml (Lu et al., 2004).

Lucidenic acids isolated from Ganoderma lucidum (YK-02) decreased cell population growth of HL-60 leukemia cells. Treatment of HL-60 cells with lucidenic acid A, C, and N caused cell cycle arrest in the G1 phase. Lucidenic acid B-induced apoptosis involved release of mitochondria cytochrome c and subsequently induced the activation of caspase-9 and caspase-3, which were followed by cleavage of poly(ADP-ribose) polymerase (PARP). Pretreatment with a general caspase-9 inhibitor (Z-LEHD-FMK) and caspase-3 inhibitor (Z-DEVD-FMK) prevented lucidenic acid B from inhibiting cell viability in HL-60 cells (Hsu et al., 2008b). Further work by the same group has also shown that Ganoderma lucidum polysaccharides induce macrophage-like differentiation in human leukemia THP-1 cells via caspase and p53 a ctivation (Hsu et al., 2009). Ganoderma lucidum has also been shown to induce apoptosis in NB4 human leukemia cells and to affect the signal transduction kinases Akt and Erk (Calvino et al., 2010).

Ganoderma lucidum has also been shown to inhibit proliferation in a dose- and time-dependent manner and induce apoptosis in human prostate cancer cells PC-3 (Jiang et al., 2004b), and Ganoderma lucidum (Lingzhi) polysaccharides have been shown to have an inhibitory effect on cervical cancer cells (CA Ski and HeLa cells) (Chen et al., 2010).

The effects of Ganoderma lucidum on SW 480 human colorectal cancer cells have been evaluated. A fraction containing mainly polysaccharides (GLE-1), and a triterpenoid fraction without polysaccharides (GLE-2) were analyzed. The data showed that both GLE-1 and GLE-2 significantly inhibited the proliferation of SW 480 cells. The inhibitory effect of GLE-2 was much stronger than that of GLE-1. GLE-1 inhibited DNA synthesis in the cells and reduced the formation of DPPH radicals indicating that G. lucidum extracts inhibit proliferation of human colorectal cancer cells and possesses antioxidant activity (Xie et al., 2006).

Aqueous extracts of the sporophores of eight mushroom species have been assessed for their ability to prevent H2O2-induced oxidative damage to cellular DNA using the single-cell gel electrophoresis ("Comet") assay. The highest genoprotective effects were obtained with cold (20ºC) and hot (100ºC) water extracts of Agaricus bisporus and Ganoderma lucidum fruit bodies, respectively. These edible mushrooms therefore represent a valuable source of biologically active compounds with potential for protecting cellular DNA from oxidative damage (Rocha et al., 2002).

Protein extracts from selenium-enriched Ganoderma lucidum (Se-GLPr) have been reported to possess strong DNA protective effects from oxidative damage, which increased with the increase of Se content as suggested by chemiluminescence analysis, indicating indirectly that Se plays an important role in increasing the antioxidant activities of protein extracts. This was confirmed by spin-trapping experiments showing that Se-GLPr exhibited higher activities of scavenging superoxide and hydroxyl radicals than its analog, common Ganoderma lucidum extract. All Se-GLPr samples showed stronger activities of attenuating the production of superoxide radical than that of hydroxyl radical (Zhao et al., 2004). Polysaccharide extracts from Se-enriched G. lucidum have also been shown to protect DNA from hydroxyl radical oxidative damage in a dose dependent manner (Zhao et al., 2008).

A hot water extract from Ganoderma lucidum has been shown to have an antioxidative effect against heart toxicity in mice. Ganoderma lucidum exhibited a dose-dependent antioxidative effect on lipid peroxidation and superoxide scavenging activity in mouse heart homogenate. Furthermore, this result indicated that heart damage induced by ethanol showed a higher malonic dialdehyde level compared with heart homogenate treated with Ganoderma lucidum. The authors concluded that this effect of Ganoderma lucidum may protect the heart from superoxide induced damage (Wong et al., 2004).

A more recent study has examined the effects of an extract of Ganoderma lucidum for its free-radical scavenging property and for effects on liver mitochondrial antioxidant activity in aged BALB/c mice (50 and 250 mg/kg body weight for 15 days) (Cherian et al., 2009). G. lucidum increased antioxidant status in liver mitochondria of aged mice compared with the aged controls. The extract possessed significant 2,2-diphenyl-1-picrylhydrazil (DPPH), 2, 2'-azinobis (3­ethylbenzothiazolin-6-sulphonic acid) (ABTS) radical scavenging activities and ferric reducing antioxidant power (FRAP) as well as superoxide and hydroxyl radical scavenging activities.

A human toxicological study has evaluated the consumption of Lingzhi (Ganoderma lucidum) in a double-blinded, placebo-controlled, cross-over intervention study on a range of biomarkers for human health. The study investigated the effects of 4 weeks Lingzhi supplementation (1.44g Lingzhi/d; equivalent to 13.2g fresh mushroom/d) on a range of biomarkers for antioxidant status, cardiovascular disease (CHD) risk, DNA damage, immune status, and inflammation, as well as markers of liver and renal toxicity. No significant change in any of the biomarkers was found. The results showed no evidence of liver, renal or DNA toxicity with Lingzhi intake (Wachtel-Galor et al., 2004).

The anti-invasive effect of lucidenic acids isolated from a Ganoderma lucidum strain (YK-02) against human hepatoma carcinoma cells have been evaluated, with the results indicating that the lucidenic acids isolated from G. lucidum (YK-02) were anti-invasive bioactive components on human hepatoma carcinoma cells (Weng et al., 2007).

Triterpene-enriched extracts from Ganoderma lucidum have been shown to inhibit growth of human hepatoma Huh-7 cells via suppression of protein kinase C, activating mitogen-activated protein kinases (intermediates in hormonal signalling pathways) and G2-phase cell cycle arrest. In contrast, the extracts did not inhibit growth of Chang liver cells, a normal human liver cell line (Lin et al., 2003).

Three triterpene aldehydes, lucialdehydes A - C, from the fruiting bodies of Ganoderma lucidum, have been shown to have cytotoxicity against murine and human tumour cells (Lewis lung carcinoma (LLC), T-47D, Sarcoma 180, and Meth-A tumour cell lines) (Gao et al., 2002).

Polysaccharide fractions of Ganoderma lucidum have been shown to have potent immunomodulating effects in pre-clinical trials. A clinical study of healthy volunteers demonstrated that G. lucidum did not affect their immune functions. Subsequently, an open-labeled study (i.e. not double blind or placebo controlled) aimed to evaluate the effects of water-soluble G. lucidum polysaccharides (Ganopoly) in patients with advanced colorectal cancer. Forty-seven patients were enrolled and treated with Ganopoly at 5.4 g/day for 12 weeks. In 41 assessable cancer patients, treatment with Ganopoly tended to increase mitogenic reactivity to phytohemagglutinin (Gao et al., 2005). Larger double blind trials are required to show if this is a real effect.

High immunomodulatory and protective effects against sarcoma 180 in mice fed with Ling Zhi or Reishi mushroom Ganoderma lucidum (W. Curt.: Fr.) P. Karst. (Aphyllophoromycetideae) mycelium has also been reported (Rubel et al., 2008). Ganoderma lucidum (Leyss: Fr) Karst. has also been shown to trigger immunomodulatory effects and reduce nitric oxide synthesis in Swiss male mice (Rubel et al., 2010). Phenolic compounds present in mushroom extracts from G. lucidum have also been shown to strongly generate reactive oxygen species (suggesting immunomodulatory effects) in human PBMCs and K 562 cells in vitro (Wei et al., 2008). Gandoderma lucidum extracts have also been shown to promote immune responses in normal BALB/c mice (Chang et al., 2009a) and WEHI-3 leukemic BALB/c mice (Chang et al., 2009b).

The polysaccharide (PS) fractions from several medicinal herbs have been reported to have anti­ulcer effects against experimental ulcers in the rat. The water-soluble PS fractions from Ganoderma lucidum (Reishi mushroom) have been shown to inhibit indomethacin-induced gastric mucosal lesions in rats. The effect of the PS fraction from G. lucidum on the healing of gastric ulcers induced by acetic acid in the rat has subsequently been studied. The results indicated that oral administration of G. lucidum PS at 0.5 and 1.0g/kg for 2 weeks caused a significant acceleration of ulcer healing by 40.1% and 55.9%, respectively. In mechanistic studies, additional rats were treated with 10M acetic acid to induce acute ulcers, and then treated with G. lucidum PS (1.0g/kg) for 3, 7, 10, or 14 days. Treatment with G. lucidum PS at 1.0 g/kg significantly suppressed or restored the decreased gastric mucus levels and increased gastric prostaglandin concentrations compared with the control group. The results indicated that G. lucidum PS is an active component with healing efficacy on acetic acid-induced ulcers in the rat, which may represent a useful preparation for the prevention and treatment of peptic ulcers (Gao et al., 2004).

Ganoderma lucidum, as well as Phellinus rimosus, Pleurotus florida and Pleurotus pulmonaris, have been reported to have significant antioxidant activities (Ajith and Janardhanan, 2007).

Cholesterol-lowering properties of Ganoderma lucidum have been demonstrated in vitro, ex vivo, and in hamsters and mini-pigs. Organic fractions containing oxygenated lanosterol derivatives inhibited cholesterol synthesis in T9A4 hepatocytes. In hamsters, 5% Ganoderma lucidum did not affect low density lipoprotein (LDL) but decreased total cholesterol (TC) by 9.8%, and high density lipoprotein (HDL) by11.2%. Ganoderma lucidum (2.5 and 5%) had effects on several faecal neutral sterols and bile acids. In mini-pigs, 2.5% Ganoderma lucidum decreased TC, LDL- and HDL cholesterol 20, 27, and 18%, respectively, increased faecal cholestanol and coprostanol; and decreased cholate (Berger et al., 2004).

The hypolipidemic effect of the exo-biopolymer (EXBP) and endo-biopolymer (ENBP) produced from a submerged mycelial culture of Ganoderma lucidum has been investigated in dietary-induced hyperlipidemic rats. Hypolipidemic effects were achieved in both the EXBP- and ENBP-treated groups, however, the former proved to be more potent than the latter. The administration of the EXBP (100mg/kg body weight) substantially reduced the plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, phospholipid levels, and atherogenic index by 31.0%, 39.0%, 35.4%, 28.1%, and 53.5%, respectively, when compared to the control group. The EXBP also lowered the liver total cholesterol, triglyceride, and phospholipid levels by 22.4%, 23.1%, and 12.9%, respectively. Furthermore, the high-density lipoprotein (HDL) cholesterol and ratio of HDL cholesterol to total cholesterol were significantly increased (Yang et al., 2002b).

Possible immuno-modulating effects of Ganoderma lucidum mycelium extract (GL-M) and spore extracts on human immune cells have been studied. Dendritic cells (DCs) are antigen-presenting cells and their role in DC-based tumour vaccines has been well defined. The differential effect of GL-M and GL spore extract (GL-S) on proliferation and Th1/Th2 cytokine mRNA expression of human peripheral blood mononuclear cells (PBMCs) and monocytes has been evaluated. The effects on the phenotypic and functional maturation of human monocyte-derived DCs were also investigated. GL-M induced the proliferation of PBMCs and monocytes, whereas GL-S showed a mild suppressive effect. Both extracts stimulated Th1 and Th2 cytokine mRNA expression, but GL­M was a relatively stronger Th1 stimulator. In contrast to GL-S, GL-M enhanced maturation of DCs in terms of up-regulation of CD40, CD80, and CD86, and also reduced fluorescein isothiocyanate­dextran endocytosis. Interestingly, GL-M-treated DCs only modestly enhanced lymphocyte proliferation in allogenic mixed lymphocyte culture with mild enhancement in Th development. The data provide evidence that GL-M has immuno-modulating effects on human immune cells and may be of use as a natural adjuvant for cancer immunotherapy with dendritic cells (Chan et al., 2005). Ganoderma lucidum has also been shown to enhance the expression of CD40 and CD80 molecules on human peripheral blood monocytic cells derived from both sexes in a dose-dependent manner (Ahmadi and Riazipour, 2009).

A polysaccharide purified from Ganoderma lucidum has also been shown to induce gene expression changes in human dendritic cells and promotes T helper 1 immune response in BALB/c mice (Lin et al., 2006).

Ganoderma lucidum mycelia (0.2-1.6mg/ml) have also been reported to stimulate tumour necrosis factor-alpha (TNF-alpha) and IL (interleukin)-6 production after 8h of treatment in human whole blood. IFN (interferon)-gamma release from human whole blood was also enhanced after 3 days of culture with Ganoderma lucidum mycelia (0.2-1.0mg/ml). However, Ganoderma lucidum mycelia did not potentiate nitric oxide production in RAW264.7 cells. An electrophoretic mobility shift assay revealed that the Ganoderma lucidum mycelia (1.6mg/ml) activated kappaB DNA binding activity in RAW264.7 cells. These results provide supporting evidence for the immunomodulatory effect of Ganoderma lucidum mycelia (Kuo et al., 2006).

An extract from Ganoderma lucidum has been reported to have apoptotic and anti-inflammatory functions in HT-29 human colonic carcinoma cells. Ling Zhi extract (LZE) is a herbal mushroom preparation that has been shown to induce apoptosis anti-inflammatory action and differential cytokine expression during induced inflammation in the human colonic carcinoma cell line, HT-29. The extract caused no cytotoxicity in HT-29 cells at doses less than 10,000 µg/ml. Increasing concentrations reduced prostaglandin E2 production, but increased nitric oxide production. LZE treatment induced apoptosis by increasing the activity of caspase-3. RT-PCR showed that LZE at a concentration of 5,000 µg/ml decreased the expression of cyclooxygenase-2 mRNA. Among 42 cytokines tested by protein array in this study, supplementation of LZE at doses of 500 and 5,000 µg/ml to HT-29 cells reduced the expression of interleukin-8, macrophage inflammatory protein 1­delta, vascular epithelial growth factor, and platelet-derived growth factor. These results suggest that LZE has pro-apoptotic and anti-inflammatory functions, as well as inhibitory effects on cytokine expression during early inflammation in colonic carcinoma cells (Hong et al., 2004).

The potential of an Ganoderma lucidum extract as a radioprotector and antioxidant defense against oxygen radical-mediated damage has been studied and it was demonstrated that a hot-water extract of Ganoderma lucidum had good radioprotective ability, as well as protection against DNA damage induced by metal-catalyzed Fenton reactions and UV irradiation, although the evidence was based on in vitro tests using isolated DNA. It was also found that the water-soluble polysaccharide isolated from the fruit body of Ganoderma lucidum was as effective as a hot-water extract in protecting against hydroxyl radical-induced DNA strand breaks, indicating that the polysaccharide compound is associated with the protective properties (Kim and Kim, 1999).

Reactive oxygen species have been reported to be involved in the pathogenesis of a number of age-associated human health conditions. The mitochondrial respiratory chain is a direct intracellular source of reactive oxygen species. Ganoderma lucidum (50 and 250 mg/kg) has been shown to enhance the activities of mitochondrial dehydrogenases and complex I and II of the electron transport chain in the brain of aged male Wistar rats (Ajith et al., 2009). The level of lipid peroxidation was significantly lowered in the Ganoderma lucidum treated group compared to the aged controls. The activity exhibited by the extract of Ganoderma lucidum was partially correlated to its antioxidant activity. If Ganoderma lucidum is able to improve the function of mitochondria in the aged rat brain, then further studies would be warranted to evaluate possible future applications against ageing associated neurodegenerative diseases.

An aqueous extract of Ganoderma lucidum (0.03 and 0.3g/kg) has been shown to lower the serum glucose level in obese/diabetic (+db/+db) mice after one week of treatment whereas a reduction was observed in lean (+db/+m) mice only fed with 0.3g/kg of G. lucidum at the fourth week. A higher hepatic PEPCK gene expression was found in +db/+db mice. G. lucidum (0.03 and 0.3g/kg) markedly reduced PEPCK gene expression in +db/+db mice whereas the expression of PEPCK was attenuated in +db/+m mice (0.3g/kg G. lucidum). These data demonstrate that G. lucidum consumption can provide beneficial effects in treating type 2 diabetes mellitus (T2DM) in mice by lowering the serum glucose levels through the suppression of hepatic PEPCK gene expression (Seto et al., 2009).

Ganoderma lucidum has been reported to possess both hypoglycaemic and anti-hyperglycaemic effects in Wistar rats (Mohammed et al., 2007), while Ganoderma lucidum polysaccharides have also been shown to significantly and dose-dependently increase nonenzymic and enzymic antioxidants, serum insulin level and reduce lipid peroxidation and blood glucose levels in streptozotocin-induced diabetic rats (Jia et al., 2009).

Ethanol extracts of Ganoderma lucidum have been evaluated against the ovariectomized (Ovx)­induced deterioration of bone density in 11-week-old female Sprague Dawley (SD) rats (Miyamoto et al., 2009). The results showed that the G. lucidum-treated Ovx rats showed improved bone density compared with the Ovx rats.

The evidence for the anti-cancer effects of Ganoderma lucidum has been reviewed (Yuen and Gohel, 2005), while the active compounds in G. lucidum and their effects have also been reviewed (Boh et al., 2007). More recently, the pharmacological aspects, cultivation methods and bioactive metabolites from Ganoderma lucidum and their potential role in various therapeutic applications have been reviewed (Sanodiya et al., 2009)