Ganoderma lucidum, a double-walled basidiospore produced by porous basidiomycete fungi, has been used as a traditional medicine for thousands of years. It is considered a valuable Chinese medicine for strengthening body resistance, invigorating the spleen, and replenishing Qi. G. lucidum contains a variety of active ingredients, such as polysaccharides, triterpenoids, nucleosides, sterols, alkaloids, polypeptides, fatty acids, steroids, and inorganic elements, and has anticancer, anti-inflammatory, hepatoprotection, hypoglycemic, anti-melanogenesis, anti-aging, and skin barrier-repairing activity.
The review summarizes the traditional usages, distribution, active constituents, structure, and biological effects of G. lucidum, with an aim to offer directions for further research and better usage of G. lucidum as a medicinal raw material.
Ganoderma lucidum is an annual or perennial fungus of the family Ganodermataceae ( Campos Ziegenbein et al. 2006); it is commonly known as “Ling Zhi” in China. In the wild, G. lucidum mainly grows in subtropical and temperate climate regions such as Asia, Europe, Africa, and Americas (Siwulski et al. 2015). G. lucidum has a kidney-shaped cap and its upper surface is russet, with a cloud-like, ring pattern, glossy exterior, and woody texture.
G. lucidum has a systematic theoretical background in traditional Chinese medicine, and research has now confirmed that it contains over 400 bioactive compounds, including polysaccharides, triterpenoids, steroids, fatty acids, amino acids, nucleosides, proteins, and alkaloids (Cör et al. 2018). Polysaccharides and triterpenoids are the major bioactive compounds in G. lucidum. The active ingredients and relative pharmacological activities differ during the different growth stages of G. lucidum. Modern pharmacology has shown that G. lucidum has antitumor (Kao et al. 2016), anti-inflammatory (Liu et al. 2018), and antioxidation effects (Sarnthima et al. 2017) and that it could regulate the respiratory, nervous, and immune systems (Kubota et al. 2018). G. lucidum also has a hypoglycemic effect (Tian et al. 2018) and can protect the liver (Wu et al. 2016). Nowadays, G. lucidum is used as a powder, tea, and dietary supplement. Therefore, it is extremely significant to study the pharmacological effects and safety of G. lucidum.
G. lucidum plays a role in inhibiting tyrosinase activity and tyrosine-related protein expression, and thus, it may ameliorate pigmentation effect (Zhang et al. 2011). It can also anti-aging by inhibiting ultraviolet B (UVB)-induced matrix metalloproteinase (MMP)-1 expression and increasing procollagen expression (Lee et al. 2018). G. lucidum also has a marked ability to scavenge free radicals in vivo.
In this review, the traditional pharmacological uses, distribution, main chemical constituents, and pharmacological effects of G. lucidum have been summarized. Furthermore, the application of G. lucidum in clinic was prospected with an aim to provide references for further development of G. lucidum-based resources.
Distribution and cultivation of G. lucidum
Distribution of G. lucidum
G. lucidum, a medical fungus, grows in subtropical and temperate climate regions such as Asia, Europe, Africa, and Americas in the wild (Siwulski et al. 2015). In Asia, G. lucidum mainly grows in China, Korea, and Japan. In Europe, it is distributed in Sweden, Denmark, and Poland. G. lucidum is distributed in Kenya, Tanzania, and Ghana in Africa (Wang et al. 2012). In China, G. lucidum grows in the regions around Yangtze and Yellow rivers (Chen and Li 2004). It originated from the Dabie Mountains, which recorded in Compendium of Materia Medica.
Cultivation of G. lucidum
Owing to the varying quality of G. lucidum in the wild and the increasing demand for it in the food service, pharmaceutical, cosmetics, and health product industries, cultivation has become a major source of the mushroom. Different active substances have been extracted from the fruiting bodies, mycelia, and spores of G. lucidum. The fruiting bodies of G. lucidum have been commonly cultivated on hardwood logs, stumps, and sawdust (Cilerdzic et al. 2018). Artificial cultivation of G. lucidum takes a long time, and its quality is susceptible to environmental conditions. Liquid- and solid-state fermentation are popular for the production of mycelia (Zhou et al. 2012), and the secondary metabolites of G. lucidum can be obtained quickly by fermentation technology.
Traditional uses of G. lucidum in China
According to the colors of the fruiting bodies, G. lucidum can be classified into red, black, blue, white, yellow, and purple Reishi, and red Reishi (G. lucidum) has shown the most significant health-enhancing effects (Cör et al. 2018). G. lucidum has been extensively used as a traditional medicine to promote health and longevity in China. In traditional Chinese medicine, G. lucidum is regarded as a valuable for strengthening body resistance, invigorating the spleen, and replenishing Qi. G. lucidum was first recognized more than 2400 years ago in Shen Nong’s Materia Medica, and the book records that G. lucidum can improve eyesight, nourish liver qi, improve vital essence, and strengthen bones and muscles. Further, in Compendium of Materia Medica, G. lucidum has been recorded as being able to preserve the spirit and longevity. Modern studies have shown that G. lucidum polysaccharides (GLPs) and Ganoderma triterpenoids (GTs) which improve immunity and exert anti-aging effects are the main contributors to the traditional pharmacological activities of G. lucidum. G. lucidum has been included in the Chinese Pharmacopoeia and in the American Herbal Pharmacopoeia and Therapeutic Compendium (Hapuarachchi et al. 2018).
Active compounds of G. lucidum
Modern studies have shown that G. lucidum contains many active compounds, including triterpenoids, polysaccharides, steroids, fatty acids, amino acids, nucleosides, proteins, and alkaloids. The triterpenoids and polysaccharides have attracted considerable attention because of their high content in the fungus, diverse structures, and significant bioactivities.
Polysaccharides are extracted from the mycelium, fruit body, and fermentation liquid of G. lucidum. The different growth stages of G. lucidum are marked by different components, structures, molecular weights, and effects of GLPs. The content of polysaccharides in the mycelium is the highest while that in the fruiting body is the lowest. The monosaccharides in the fruiting bodies are mainly glucose and galactose, while that from the mycelium and spores is mainly glucose (Khanna et al. 2012). GLPs extracted from fruiting bodies can exert anticancer effects via immunomodulation. Various types of polysaccharides, with molecular weights ranging from 4 × 105 to 1 × 106 Daltons (Bishop et al. 2015), have been identified in the fruiting body and mycelia of G. lucidum (Khanna et al. 2012; Ferreira et al. 2015). The basic framework of GLPs comprises a high-molecular-weight β-(1→3)-d-glucan with (1→6)-β-d-glucosyl branches (Liu et al. 2014), and the main components of sugars are mannose, rhamnose, glucose, and galactose.
More than 200 triterpenes have been identified from the fruiting bodies, spores, and mycelia of G. lucidum (Baby et al. 2015; Xia et al. 2014). The fruiting body of G. lucidum has a high content and wide variety of GTs, while the mycelium has few GTs species. GTs have not be detected in non-broken spores of G. lucidum (Yu et al. 2016). All triterpenes are tetracyclic triterpenes (Xia et al. 2014). According to the functional groups and side chains, GTs can be divided into compounds including ganoderic acid, ganoderiol, ganoderone, ganolactone, and ganoderal (Baby et al. 2015). The skeletal types of Ganoderma triterpenoids in G
Proteins and polypeptide
Several bioactive proteins from G. lucidum have been reported. Ling Zhi-8 (LZ-8) is a polypeptide consisting of 110 amino acid residues with an acetylated amino terminus (Lin et al. 2011). The sequence and predicted secondary structure of LZ-8 is very similar to the variable region of the heavy chain of immunoglobulins. LZ-8 was the first immunomodulatory protein obtained from the mycelial extract of G. lucidum by using chromato-graphic and electrophoretic techniques (Ahmad 2018).
β-N-Acetylhexosaminidase, α-1,2-mannosidase, endo-β-1,3-glucanase, β-1,3-glucanase, and glutamic protease were extracted from G. lucidum, and glutamic protease is the major protein in the extracts of G. lucidum (Kumakura et al. 2019).
G. lucidum also contains nucleosides such as adenosine, cystidine, guanosine, inosine, thymidine, and uridine as well as nucleotides, including adenine, guanine, hypoxanthine, thymine, and uracil (Gao et al. 2007).
Vitamins and minerals
Several vitamins have been reported from G. lucidum, such as vitamins B1, B2, B6, β-carotene, C, D, and E. Moreover, various minerals such as calcium, sodium, potassium, phosphorus, iron, carbon, magnesium, zinc, chromium, arsenic, copper, manganese, silicon, aluminum, cobalt, molybdenum, nickel, and lead have been identified in G. lucidum (Ahmad 2018).
Physiological activity of G. lucidum
Modern medical research has shown that G. lucidum contains a variety of compounds with anticancer (Kao et al. 2016), hypoglycemic (Yang et al. 2018), liver protection (Zhao et al. 2019), and anti-inflammatory (Hasnat et al. 2015) effects. Studies also suggest that G. lucidum possesses strong antioxidant (Lee et al. 2016) anti-melanogenesis (Hsu et al. 2016), anti-aging (Zeng et al. 2017), and skin barrier-repairing (Montalbano 2018) properties. Thus, G. lucidum is important as the lead for the development of pharmaceuticals, nutraceuticals.
It has been reported that GLPs, GTs, and extracts of G. lucidum have inhibitory effects on cancers, such as prostate cancer (Kao et al. 2016), lung cancer (Chen et al. 2016), glioma (Wang et al. 2018), breast cancer (Smina et al. 2017), and malignant melanoma (Zheng et al. 2018). The underlying mechanisms for the inhibition of these tumors have also been elucidated.
Whiskey and rice wine extracts of G. lucidum with growth inhibitory effects against prostate cancer cell lines were identified. The extracts exerted their effects by inhibiting the cell cycle, inducing apoptosis, and reducing tumor progression (Kao et al. 2016). An ethanol extract of sporoderm-broken spores of G. lucidum arrested the cell cycle at the G2/M phase and triggered apoptosis by decreasing the expression and activity of cell cycle regulators. It inhibited the survival and migration of human lung cancer cells in a dose-dependent manner, through inhibition of the protein kinase B (Akt) and mammalian target of rapamycin (mTOR) signaling pathway (Chen et al. 2016).
The antitumor effects of GLPs were evaluated on the immune system of rat models of glioblastoma. GLPs increased the concentration of serum interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ); the cytotoxic activity of natural killer and T cells; and the functional maturation of dendritic cells, thus resulting in the inhibition of glioma growth (Wang et al. 2018). Total triterpenes induced apoptosis in human breast adenocarcinoma cells by downregulating the levels of cyclin D1, B cell lymphoma-2 (Bcl-2), AND B cell lymphoma-extra large (Bcl-xL) and upregulating the levels of Bax and caspase-9 (Smina et al. 2017). 9,11-Dehydroergosterol peroxide from G. lucidum mycelium inhibited human malignant melanoma cells by participating in the process of decreasing the expression of the myeloid leukemia cell differentiation protein Mcl-1, damaging the mitochondrial membrane, and releasing cytochrome-c (Zheng et al. 2018).
The above studies confirmed that the alcohol extract, total triterpenes, and GLPs have antitumor activity. GTs inhibited cytotoxicity by inhibiting the proliferation and metastasis of cancer cells. G. lucidum used as supplements in cancer chemoprevention and chemotherapeutic regimens could be beneficial for the treatment and prevention of various cancers as an adjunct therapy.
The active ingredients in G. lucidum, such as GLPs and GTs, can act on the immune system and effectively exhibit hepatoprotective effects and treat liver damage. The hepatoprotective effects of G. lucidum have been widely studied. GLPs can protect hepatocyte injury induced by CCl4 by inhibiting lipid peroxidation, elevating antioxidant enzyme activity, and suppressing apoptosis and immune inflammatory response (Liu et al. 2015). GTs can significantly increase the relative cell viability by 13.46% and reduce the levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase by 51.24%, 33.64%, and 24.07%, respectively, in a culture medium. GTs offered significant cytoprotection against the oxidative damage induced by tertbutyl hydrogen peroxide (t-BHP) in hepatocellular carcinoma cells by decreasing the level of malondialdehyde and increasing the contents of glutathione and superoxide dismutase (SOD) (Wu et al. 2016). Ganoderma submerged fermentation reduced ethanol-induced steatohepatitis by decreasing the expression of inflammatory mediators (Chung et al. 2017). Analysis of histopathology and serum enzymes in mice revealed an important hepatoprotective function for the ethanol extract of G. lucidum (GLE). GLE inhibited lipid peroxidation, elevated the activity of antioxidant enzymes, and suppressed apoptotic cell death and immune inflammatory responses. It was therefore assumed that GLE can improve alcohol-induced liver injury (Zhao et al. 2019). Previous studies have concluded that G. lucidum protects hepatocytes from damage by inhibiting lipid peroxidation and decreasing the expression of inflammatory mediators.
In recent years, the antidiabetic components and hypoglycemic mechanisms of G. lucidum have been studied. Protein tyrosine phosphatase 1B (PTP1B) is a therapeutic target in diabetes. A novel proteoglycan, called Fudan-Yueyang-G. lucidum (FYGL), has been extracted from G. lucidum. FYGL has dose-dependent hypoglycemic and hypolipidemic effects and could increase blood insulin levels. Furthermore, it inhibited the overexpression of PTP1B, enhanced insulin-stimulated glycogen synthesis, and decreased blood glucose in a mouse model of insulin resistance (Tian et al. 2018). FYGL can ameliorate type 2 diabetes mellitus caused by mitochondrial dysfunction and can decrease ROS level (Yang et al. 2019).
In addition, GLPs can downregulate the activity of hepatic glucose-regulated enzymes and epididymal fat/BW ratio and improvement of insulin resistance (Xiao et al. 2017). The results demonstrated that GLPs have significant hypoglycemic properties and that it may be an effective dietary food for the prevention and treatment of obesity and diabetes.
Inflammation is a normal physiological response to an infection or injury, which is part of host defense and tissue healing (Lee and Choi 2018). In the inflammatory environment of the body, elevated levels of TNF-α, IFN-γ, and IL-4 can further accelerate the inflammatory response in the dermis and destroy epidermal barrier function. GLPss58, a sulfated form of a polysaccharide from the fruiting body of G. lucidum, can inhibit the binding of L-selectin with the receptor, activate the complement systems, and block the binding of TNF-α and INF-γ to their antibodies. GLPss58 could inhibit all the L-selectin-, complement-, and cytokine-mediated inflammation pathways (Zhang et al. 2018a, 2018b). In addition, GLPs can prevent inflammation, maintain intestinal homeostasis, and regulated the intestinal immunological barrier functions in mice by markedly suppressing the secretions of TNF-α, IL-1β, IL-6, and IL-4 (Wei et al. 2018). The anti-inflammatory effect of GLPs plays an important role in clinic for sensitive skin.
Effect on the skin
G. lucidum has been an important functional ingredient in many salve formulations due to its anti-aging, anti-melanogenesis, and skin barrier-enhancing properties.
The abnormal accumulation of melanin causes skin pigmentation. Tyrosinase is an enzyme that regulates melanin synthesis. G. lucidum can inhibit the activity of tyrosinase and tyrosine-related proteins, which prevents hyperpigmentation. Methyl lucidenate F isolated from G. lucidum showed a dose-dependent tyrosinase inhibitory activity, with an IC50 of 32.23 μM (Zhang et al. 2011). On the other hand, the cAMP-dependent signaling pathway regulates melanogenesis by inhibiting cellular phosphorylation of the cAMP-responsive element-binding protein (CREB). Thus, downregulating the expression of microphthalmia-associated transcription factor (MITF) decreases melanin production (Liu et al. 2015). The active compound Ganoderma mannitol was obtained from G. lucidum. Compared to arbutin (0.5 mM), ganodermanondiol (10 μM) significantly reduced the melanin content in B16F10 melanoma cells. Furthermore, the inhibitory effect of ganodermanondiol contributed to the reduction in MITF expression and melanin production through the inhibition of CREB phosphorylation. The phosphorylation of extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) downregulated melanin synthesis, but phosphorylation of p38 triggered MITF expression and melanin production. Ganodermanondiol induced the phosphorylation of ERK and JNK suppressed the phosphorylation of p38 (Kim et al. 2016). GLPs are different from GTs in that they can directly affect melanogenesis in melanocytes. GLP can antagonize UVB-induced skin pigmentation in vivo (Hu et al. 2019a, 2019b). GLP can inhibit the paracrine effects of keratinocytes and fibroblasts via the fibroblast growth factor (FGF2)/MAPK pathway to decrease melanogenesis in melanocytes (Jiang et al. 2019). G. lucidum can treat pigmentary dermatosis such as solar lentigo, chloasma, freckles, and senile plaques.
Antioxidant and anti-aging activity
UV is a primary environmental factor implicated in skin aging; it causes coarse wrinkling, dryness, and laxity (Kong et al. 2018). UVB irradiation stimulates MMP-1 secretion and reduces the synthesis of collagen and elastin, which can accelerate skin senescence (Hwang et al. 2018). The extract of G. lucidum can inhibit UVB-induced MMP-1 expression and increased procollagen expression by inhibiting ERK pathways (Lee et al. 2018). GLPs can inhibit MMP-1 protein expression, promote C-telopeptides of type I collagen protein, and inhibit ROS production in fibroblasts following UVB treatment (Zeng et al. 2017).
The long-term presence of free radicals and ROS accelerates aging and numerous age-associated illnesses (Bishop et al. 2015). Therefore, studies on scavenging free radicals and ROS are particularly important in anti-aging research.
The antioxidant properties of crude proteins obtained from the mycelium and fruiting bodies of G. lucidum were studied. It was found that protein from both the mycelia and fruit body exhibited antioxidant capacity. The mycelial protein extract showed better scavenging activities than those shown by fruiting body protein extract, in terms of both 2,2′-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) radical- and 2,2-diphenylpicrylhydrazyl radical (DPPH•) radical-scavenging abilities (Sa-Ard et al. 2015). Oxidative stress markers were measured by using the comet assay to measure ROS generation. Furthermore, the ethanol extract of G. lucidum could significantly reduce H2O2-induced ROS production compared to that in the positive control (Lee et al. 2016).
Skin barrier-repairing activity
A wound damages the skin barrier, which will cause microbial invasion and inflammation. G. lucidum, as a wound-healing agent, can be used to treat chronic non-healing wounds in vitro (Montalbano 2018). Nanogel containing triterpenoids isolated from G. lucidum has shown beneficial effects on the frostbite healing process by increasing the wound healing area and improving the degree of pathological change in skin tissue of rats with frostbite (Shen et al. 2016). GLP promotes the migration ability of fibroblasts and upregulates the expressions of C-terminal peptide of procollagen type I and transforming growth factor-β1 in fibroblasts, so it can heal wounds (Hu et al. 2019a, 2019b). Thus, G. lucidum can be used for barrier repair to promote wound regeneration.
Besides the above-mentioned pharmacological actions, the extract of G. lucidum can activate the AMPK/mTOR and PINK1/Parkin signaling pathways and regulate mitochondrial function, autophagy, and apoptosis, thus improving parkinsonian symptoms (Ren et al. 2018). G. lucidum can induce the secretion of immunoglobulin A and ameliorate intestinal infections (Kubota et al. 2018).
In summary, the anticancer and anti-inflammatory effects of G. lucidum have been confirmed in cell assays and signaling pathways, and especially, hypoglycemic effects have been demonstrated in mice. However, G. lucidum effects have been investigated in few clinical trials in humans. Therefore, the side effects of G. lucidum need to be further studied. Further, the melanin inhibitory, anti-aging, antioxidant, and skin barrier-enhancing properties of the secondary metabolites from G. lucidum should be focused on more in future research. G. lucidum has great potential in the development of medicines, cosmeceuticals, and nutritional supplements and the research and development of G. lucidum resources are of great significance.
G. lucidum is a traditional Chinese medicine that has been used for centuries as a nutritional supplement and herbal medication. This review summarizes the active substances of G. lucidum. Polysaccharides and triterpenoids are the major secondary metabolites of G. lucidum. The polysaccharides mostly comprise α- or β-(1→3)-, (1→6)-glucans and hetero-polysaccharides. More than 200 kinds of GTs have been isolated from G. lucidum. GTs can effectively inhibit the proliferation and metastasis of cancer cells. Ganoderic acids are the prominent bioactive constituents of GTs. Ganoderic acid A, ganoderic acid F, ganoderic acid H, ganoderic acid C, ganoderic acid D, ganoderic acid T, ganoderic acid X, and ganoderic acid Y can be used as adjuvant drugs to suppress cancer. Therefore, the application of GTs in the pharmaceutical industry is very important.
In addition, the secondary metabolites isolated from G. lucidum can be used in functional foods or medicines for properties such as anti-aging, decreased surface pigmentation, and skin barrier-enhancing effects. GTs, especially methyl aspartate and Ganoderma mannitol, have skin-whitening effects. Crude proteins obtained from the mycelia and fruiting bodies of G. lucidum show antioxidant effects. GLPs can inhibit the expression of MMP-1, increase procollagen expression, and scavenge free radicals and reactive oxygen species, which can delay aging. The human internal environment is interacted by many kinds of cells through various forms. Although the pharmacological effects of G. lucidum have been confirmed at the level of monolayer cells, monolayer cells can not simulate the multicellular environment in vivo, so the effect of G. lucidum on multicellular interconnection can not be explored. We can use cell co-culture to study the relationship between different cells in order to verify the pharmacological effect of G. lucidum.
In recent years, with the development of microbial technology, it has a good prospect to obtain GTs through microbial fermentation technology. G. lucidum has become a popular nutraceutical worldwide; it has great cosmeceutical potential. G. lucidum, as a good medicinal and food homologous medicinal material, has received more and more attention in the food health care and cosmetics industry, and its application in food health products and cosmetics has potential for further exploration.
Availability of data and materials
AMP-activated protein kinase
B cell lymphoma-2
B cell lymphoma-extra large
Cyclic adenosine monophosphate
cAMP-responsive element-binding protein
Extracellular signal regulated kinase
Fibroblast growth factor
- G. lucidum :
Extract of G. lucidum
G. lucidum polysaccharides
c-Jun N-terminal kinase
Mitogen-activated protein kinase
Microphthalmia-associated transcription factor
Reactive oxygen species
Tumor necrosis factor-α