Medicinal mushrooms are rich sources of pharmacologically active compounds. One of the mushrooms commonly used in traditional Chinese medicine is Ganoderma lucidum. In Asian countries, it is a nutraceutical whose regular consumption provides vitality and improves health. Ganoderma lucidum is an important source of biologically active compounds. The pharmacologically active fraction of polysaccharides has antioxidant, immunomodulatory, antineurodegenerative, and antidiabetic activities. This review summarizes the activity of Ganoderma lucidum polysaccharides (GLP).

  1. Antioxidative Activity

Under physiological conditions, there is a balance between forming reactive oxygen species and eliminating them by the free radical scavenging system. Excessive levels of ROS cause redox imbalances and lead to oxidative damage to the tissues. Protein, lipid, and DNA damage caused by oxidative stress and the resulting elevated levels of reactive oxygen species (ROS) are important factors in the onset and development of diseases. Medicinal fungi such as Ganoderma lucidum have antioxidant and prooxidative properties, which are used in combination therapy for some diseases. Polysaccharides isolated from G. lucidum showing antioxidant activity protect tissues against ROS toxicity and help maintain the body’s oxidative status. The Chinese Food and Drug Administration (CFDA) has approved a drug based on a polysaccharide extracted from spores of G. lucidum. This preparation is only used in China for polymyositis, dermatitis, and muscular dystrophy. It is also one of the few non-hormonal drugs used in treating refractory myopathy and in combination therapy with glucocorticoids.

According to the conducted in vivo experiments, polysaccharides from G. lucidum show anti-inflammatory and protective effects against oxidative stress in the heart, liver, spleen, and skeletal muscles. GLPs induce the synthesis of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione S-transferase (GST), mitochondrial succinate dehydrogenase (SDH) and reduce glutathione, which protects the endothelium of blood vessels. They, however, reduce nitric oxide synthase (NOS), cytochrome P450, xanthine oxidase, and myeloperoxidase, which significantly affect the dysfunction of the vascular endothelium and induce atherosclerosis. Undoubtedly, oxidative stress plays a significant role in the etiology of many metabolic diseases that disrupt the proper functioning of many organs. Prolonged oxidative stress leads to the body’s aging and the occurrence of many age-related diseases. In vivo studies have shown that GLP has a beneficial antioxidant effect due to a decrease in lipid peroxidation levels and an increase in the activity of antioxidant enzymes. Depending on the GLP dose used, the above antioxidant properties were checked in mice exposed to ɣ irradiation and cervical carcinoma in rats.

Further in vivo studies demonstrated that low molecular mass polysaccharides (GLP-1 and GLP-2) show higher antioxidant and immunomodulatory activity. Both polysaccharides were administered to mice with immunosuppression caused by cyclophosphamide administration. Polysaccharides increased the number of white blood cells and lymphocytes, which positively affected hematopoiesis. Serum IgG and IgA immunoglobulin levels were also tested, and elevated IgA was found.

This study demonstrated the immunomodulatory activity of polysaccharides naturally occurring in medicinal mushrooms. Other studies have shown the effect of two polysaccharides, GLP and GLPUD, on the activity of superoxide dismutase and glutathione peroxidase and malondialdehyde levels in the serum and liver of mice fed a high-fat diet. Polysaccharides were heteropolysaccharides, consisting mainly of glucose and significantly lower amounts of fructose, mannose, galactose, xylose, rhamnose, glucuronic acid, and galacturonic acid. Mice administered with G. lucidum extracted polysaccharides for 30 days showed increased activity of antioxidant enzymes compared to the dose of GLP. Moreover, malondialdehyde levels decreased. In many biochemical transformations, oxygen and nitrogen free radicals are created, which are highly reactive and cause mitochondrial dysfunction. The long-term effects of oxidative stress significantly accelerate the aging processes and are related to numerous neurodegenerative diseases, metabolic syndromes, and neoplasms. However, supplementation with polysaccharide preparations from G. lucidum could contribute to the improvement of our lives, which should be the goal of further searches. Further studies should focus on assessing the degree of toxicity of polysaccharide preparations and the potential of their efficacy in clinical trials. So far, the use of the polysaccharide from G. lucidum as a drug has only been approved by the CFDA.

  1. Immunomodulatory Activity

Current biochemical and clinical studies have shown that polysaccharides from Ganoderma lucidum are potent immunomodulators. The immunomodulatory activity of polysaccharides is associated with their influence on effector cells, such as macrophages, B and T lymphocytes, Natural Killer cells (NK cells), and dendritic cells. GLPs have increased T and B cell proliferation through Toll-like receptor 4 (TLR4). As a result of interactions with TLR4/TLR2 receptors, signal induction occurs through a p38 mitogen-activated protein kinase (p38 MAPK).

GLP also induces the activation and maturation of human dendritic cells derived from monocytes through NF-ĸB nuclear factor (nuclear factor κ-light-chain-enhancer of activated B cells) signaling and MAPK protein kinases. Moreover, GLP has been shown to enhance the function of chemotaxis and phagocytosis of neutrophils. These processes involve the phosphorylation of tyrosine kinases, p38 MAPK, Src (proto-oncogene tyrosine-protein kinase Src), PI3K (phosphatidylinositol 3-kinase), and protein kinase C. Cell-wall polysaccharides isolated from G. lucidum have also been shown to induce innate immune cytokines, tumor necrosis factor-α (TNF-α), interferon γ (IFN-ɣ) and interleukin-2 (IL-2) in human peripheral blood mononuclear cells (PRMC).

Macrophages are responsible for the phagocytosis of pathogens, reacting to chemokines that induce their recruitment to the site of tissue damage. Serine-threonine kinases (Akt1 and Akt2) play the most important role in regulating macrophage activation. Depending on the signaling cascades, activation stages, and stimuli of the cellular environment, macrophage polarization can be defined as M1 or M2. Classically activated macrophages (M1) produce proinflammatory and cytotoxic molecules, such as reactive oxygen species (ROS), nitric oxide, TNF-α, IL-1β, IL-6, and chemokines. The rFIP-glu polysaccharide from G. lucidum has a dose-dependent modulating effect on the activation of RAW264.7 macrophages.

These results show that the rFIP-glu recombinant polysaccharide transcriptionally regulates the expression of inflammatory mediators, TNF-α, NO, arginase II, IL-1, and IL-6, in LPS-stimulated macrophages. rFIP-glu strongly promotes polarization of M1 macrophages by initiating proinflammatory reactions while lowering IL-10, a marker of M2 macrophages. rFIP-glu polysaccharide may affect the conversion of M2 to M1, which plays a key role in treating many diseases. A study found synergistic effects of β-glucans derived from three different medicinal mushrooms on human macrophages. These preparations, also derived from G. lucidum, induced an immunostimulatory response leading to the expression of proinflammatory mediators, such as Il-1, IL-6, and TNF-α. At the same time, they reduced the expression of the anti-inflammatory cytokine IL-10. This is the first research on the synergistic immunomodulatory effects of natural preparations from medicinal mushrooms.

Therefore, the results of the above study provide mechanistic insight into the bioactivity of such complex preparations and their application in the design of bioactive drugs. Based on current scientific research, it can be concluded that Ganoderma lucidum is a promising source of nutraceuticals with broad-spectrum drug therapeutic potential. Due to the huge number of biologically active compounds, it is a potential source of natural medicinal substances with low toxicity. However, further pharmacokinetic and clinical studies are required to determine the toxicity of these compounds.

  1. Antineurodegenerative Activity

Redox imbalance in cells, as well as excessive or unregulated production of inflammatory mediators, is an element of the induction of neurodegenerative diseases, such as atherosclerosis, diabetes, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In neurodegenerative diseases, activated microglia are observed, which release proinflammatory and anti-inflammatory cytokines and neurotoxic mediators.

In a study on the LPS-induced inflammation microglia cell line treated with GLP for two hours, the expression of proinflammatory cytokines IL-1 and IL-6 and induced NO synthase (iNO) was inhibited. Further study results showed that GLP is also a potent inhibitor of amyloid β (Aβ) stimulated primary mouse microglia (Aβ), which may indicate modulation of neurological inflammation. GLP also significantly increased the expression of the anti-inflammatory cytokine TGFβ in both the microglia cell line (BV2) and the primary microglia cell line.

Based on the above in vitro studies, it can be assumed that GLP may act in the early stages of Alzheimer’s disease to reduce inflammation. In a similar study, the effect of G. lucidum fruiting body extract (GLE), which contained a large polysaccharide fraction, was tested on the BV2 cell line. GLE declines the level of proinflammatory cytokines in cells by modulating the signaling pathways of NF-ĸB and MAP kinases that regulate the synthesis of proteins involved in inflammatory processes.

Therefore, it is highly probable that G. lucidum fruiting body extract can also play a role in preventing neurodegenerative diseases by modulating signaling pathways. Recent studies have shown that polysaccharides from G. lucidum have neuroprotective effects and impair neurotoxicity induced by β amyloid peptide. Further reports found that administering GLP to rats protects their hippocampus against oxidative damage. These data initiated the possibility of polysaccharides in treating Alzheimer’s disease.

Activated microglia release pro- and anti-inflammatory cytokines and cytotoxic mediators. Microglia can remove dead neurons due to phagocytosis but also cause the death of live neurons by phagoptosis. Phagoptosis is involved in the loss of neurons during neurodegeneration of the brain. Microglia act as the main immune defense in the central nervous system (CNS).

In the active phase, phagocytic microglia migrate and accumulate at the injury site. Microglia is the brain macrophage and can remove apoptotic cells. Polysaccharides extracted from G. lucidum significantly reduced amyloid-induced neurotoxicity. Further work demonstrated the G. lucidum spore effect on rat hippocampus, which protected against oxidative damage.

Another significant finding was that GLP could inhibit microglial activation in rats with Parkinson’s disease. Another important process underlying aging and age-related diseases is the gene methylation cycle. Measurements of genome hypomethylation and hypermethylation of specific genes are emerging in understanding the aging processes. In this direction, a study was carried out on the effects of alcohol extracts of triterpenes and polysaccharides from G. lucidum on the regulation of DNA methylation in rats with induced aging. Aging was induced by intraperitoneal administration of D-galactose for eight weeks. Elevated DNA methyltransferase levels and improved morphology of hippocampal pyramidal cells were found in brain tissues after treatment with alcohol extracts from G. lucidum.

Histochemical results have shown that the extracts can positively affect neuronal apoptosis and brain atrophy and reduce the expression of the Alzheimer’s marker, β-amyloid (Aβ1-42). Based on the above study, it can be concluded that alcohol extracts from G. lucidum can regulate DNA methylation, which affects the progression of Alzheimer’s disease. Further research into DNA methylation will help elucidate the mechanism behind these processes.

  1. Antidiabetic Activity

The long-term effects of diabetes reveal the dysfunction and failure of many organs. Many experiments have shown that animals with induced diabetes have a higher level of oxidative stress, and redox imbalance is closely related to disease development. The organism’s antioxidant system should balance ROS formation and the free radical scavenging system. From animal studies with streptozotocin-induced diabetes, it was found that the antioxidant, both enzymatic and nonenzymatic systems, were significantly impaired. This concerned the activity of free radical scavenging enzymes, SOD, GPx, CAT, and oxidative stress. The polysaccharides from G. lucidum acted as exogenous antioxidants and restored the endogenous redox balance by reducing malondialdehyde levels and inducing the expression of antioxidant enzymes.

Studies of ultrastructural changes in pancreatic β cells also confirmed damage to these cells in a group of animals with induced oxidative stress and diabetes. External oxidative stress significantly affected the redox balance and damaged the mitochondria. However, after applying the polysaccharide (GLPs) to a group of animals, the ultrastructure of the mitochondria of the pancreatic islet cells was maintained by restoring the redox balance.

Excessive production of ROS in cells damages the mitochondrial membrane, oxidizes proteins and introduces mutations in DNA, which ultimately causes mitochondrial dysfunction. Most of the endogenous ROS are of mitochondrial origin and indirectly contribute to the development of insulin resistance. Natural extract of the polysaccharide from G. lucidum also reduced insulin resistance and damage to pancreatic islet cells. It successfully reversed the entire process of diabetes development along with the prolonged duration of action.

The above studies suggest that in future clinical trials, which are lacking regarding polysaccharides from G. lucidum, the level of oxidative stress, the dose of the polysaccharide, and the duration of its action on the given tissue should be taken into account. Oxidative stress, which occurs in the early stages and at physiological glucose levels, plays a key role. Recent studies in rats with induced diabetes have shown that GLP supplementation reduces inflammation and increases the beneficial intestinal microflora that protects the organism against infections.

These results provide further insight into the beneficial effects of the polysaccharide from G. lucidum on the regulation of metabolism and modulation of intestinal dysbiosis. Nonenzymatic glucose reactions with proteins or lipids lead to the formation of advanced glycation end products (AGE) that disturb the organism’s biochemical and physiological functions. Current therapies have limited effectiveness, tolerance, and significant side effects. Therefore, interest in natural treatments is increasing. The most exciting finding was that G. lucidum polysaccharides are safe and effective as antioxidants.

Another important finding was that polysaccharides have an antihyperglycemic effect. To this end, water extracts from G. lucidum were also tested, reflecting normal daily consumption of mushrooms. It was found that administering water extracts to laboratory animals with induced diabetes significantly reduced blood glucose levels. The hypoglycemic effect of polysaccharides has been extensively studied in vitro and in vivo. The hypoglycemic effect of polysaccharides from G. lucidum was found in rats with streptozotocin-induced diabetes. GLP also had the ability to relieve morphotic changes in the kidneys and reduce oxidative stress. This study found GLP to cause hypolipidemic effects, significantly reducing total cholesterol and triglycerides. The polysaccharide from G. lucidum administered to insulin-resistant rats improved vascular endothelial dysfunction. There was a decrease in the levels of hydrogen peroxide, triglycerides, and total cholesterol, which significantly enhanced the vascular endothelium.

Genetic and environmental conditions, as well as bacterial microflora, play an important role in diabetes. A strong relationship between diabetes mellitus and intestinal dysbiosis has been reported in the literature. Current research indicates that GLP has an effect on intestinal dysbiosis that has been associated with type 2 diabetes. Intestinal dysbiosis mediates immune disorders, chronic inflammation, and the development of diabetes mellitus through abnormal production of its metabolites.

As a result of treatment with polysaccharide from G. lucidum for four weeks, the level of beneficial bacteria increased, and the hyperglycemia and hyperlipidemia were alleviated in type 2 diabetic rats. Bioactive polysaccharides represent new strategies for treating disorders associated with metabolic diseases. After all, potential pharmacological approaches to circumvent the harmful effects of oxidative stress by reducing exogenous and endogenous sources of free radicals, inhibiting the inflammation induced by them, and including the use of antioxidant polysaccharides from G. lucidum are extremely promising.