Bioactive Molecules in Edible and Medicinal Mushrooms for Human Wellness
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Mushrooms are now gaining popularity not only as an ordinary culinary ingredient, but as a healthy and whole functional food. This chapter describes three major categories of bioactive molecules found in edible and medicinal mushrooms. First is the mushroom’s polysaccharide which is widely accepted as a superior immune-modulatory agent. The mushroom β-glucans differ from the bacterial and plant glucans. Mushroom β-glucans consist of linear β-(1→3)-linked backbones with β-(1→6)-linked side chains of varying length and distribution. Several important β-glucans like lentinan, schizophyllan, grifolan, as well as polysaccharide krestin (PSK) and polysaccharopeptide, will be discussed. Next, the triterpenes family, which are highly conserved in Ganoderma species, will be elaborated further in this chapter. Finally, the indole alkaloids, which are important in mushroom as pigmentation inducer and hallucinogens, will be briefly discussed with emphasis on the psilocin and its derivatives. Other pharmacologically important mushroom-derived alkaloids will also be included. Overall, the potential to develop mushrooms as nutraceutical foods for human wellness, and their bioactive molecules for drugs, is huge.
KeywordsMushroom Polysaccharide Glucans Triterpenes Alkaloid Indole
In terms of food, mushroom consumption is considered popular in six countries known as the G-6 (USA, Germany, UK, France, Italy, and Canada) . The six countries make up to 85% of the world consumption of mushroom. According to the Food and Agriculture Organization (FAO), the main exporters of fresh mushrooms in 2012 are Poland, Netherlands, China, Ireland, and Canada. The main importers of fresh mushrooms in the world are the United Kingdom, Germany, Russia, France, and USA. To date, China is still the main producer of mushrooms in the world, producing 5.15 million tons of fresh and processed products yearly.
Indeed, there are many other important roles that mushrooms play in the world. Their expediency to man as food, as tonics and medicines, and also in the bioconversion of waste organic materials are all of great benefit to both man and nature . Phan and Sabaratnam  have recently reviewed that the spent mushroom substrate can serve as a reservoir to recover important lignocellulosic enzymes like laccase , xylanase, lignin peroxidise, cellulose, and hemicellulase. In recent years, mushrooms are also known as “mycoremediation tools” because of their use in remediation of different types of pollutants [8, 9].
The six mushroom species which are highly researched on their antitumor/anticancer activities. The most recent literature on the antitumor/anticancer properties of these mushrooms is included along with this table.
Effectively inhibited tumor growth in Hepa1-6-bearing C57 BL/6 mice
Ganoderic acid A
Ganoderic acid B
Ganoderic acid C2
Ganoderic acid D
Ganoderic acid H
Ganoderic acid Y
Ganoderenic acid A
Ganoderenic acid D
Ganoderenic acid G
The mushroom polysaccharides enhanced the radiosensitivity of hepatocellular carcinoma cell line HepG2 through Akt signaling pathway
Inhibited the proliferation of human prostate cancer cells and induced apoptosis
Inhibited prostate cancer cell migration
Dongchongxiacao, caterpillar mushroom, winter caterpillar summer grass
Inhibited malignant transformation, increased cell apoptosis, and decreased cell mitosis in a murine oral cancer model
Induced apoptotic cell death of human brain cancer
Chaga mushroom, black tree fungus
Inhibited NF-κB nuclear translocation in human nonsmall cell lung carcinoma (NSCLC)
Lanostane-type triterpene (inonotusanes D)
Exhibited strong cytotoxicity against the 4T1 (mouse breast cancer) cell line
Exhibited inhibition of cell proliferation on HCT-116 and HeLa cells
Showed inhibition against A549 human lung cancer cells, SGC7901 gastric cancer cells, MCF-7 breast cancer cells, U937 histiocytic lymphoma cells, and MG-63 human osteosarcoma cells
Cytotoxic against PC3 and HeLa cancer cells
Yunzhi, maitake mushroom, hen of the woods
Showed synergistic effects with vitamin C against SMMC-7721 hepatocarcinoma cells
Modulated mammary tumor progression
Enhanced immunostimulatory activity
Extracts combined with metronomic zoledronic acid
Attenuated breast tumor propagation
Exhibited antitumor activity on Sarcoma-180 cells
In this chapter, we describe and emphasize on the highly sought after bioactive compounds (polysaccharides, triterpenes, and alkaloids) isolated from mushrooms. We also report on the recent advances in our understanding of these mushroom-derived compounds as well as their mode of actions.
2 Abundance of Nutraceuticals in Mushrooms
The involvement and importance of polysaccharides in tumor and cancer treatment were first recognized more than 100 years ago when it was found that certain polysaccharides could induce complete remission in patients with cancer. Ever since antitumor activity of macrofungal polysaccharides was first published by Chihara in the 1960s , researchers have isolated structural diversified polysaccharides with strong antitumor activity . Unlike traditional antitumor drugs, these substances produce an antitumor effect by activating various immune responses in the host and cause no harm to the body .
Carrying out an extensive study in 1966, Gregory isolated the active substances from fruiting bodies of more than 200 Basidiomycetes mushroom species . The polysaccharides isolated from 22 mushroom species and 50 culture media displayed an inhibitory effect on tumor cells, including Sarcoma S-180, adenocarcinoma 755, and leukemia L-1210 [36, 37]. Bioactive polysaccharides can be isolated from mycelium , the fruiting body, and sclerotium , which represent three different forms of a macrofungi in the life cycle [38, 39].
Most recently, Ahn et al.  studied the effects of lentinan from L. edodes on mouse bone marrow-derived macrophages with and without inflammasome triggers. Lentinan was found to upregulate pro-inflammatory cytokines like interleukin (IL)-1β, IL-18, or caspase-1. However, lentinan was found to attenuate IL-1β secretion when the macrophages were treated with bacteria Listeria monocytogenes or lipopolysaccharide (LPS). This clearly shows that lentinan, a bioactive polysaccharide, can act as a “double edge sword.” It increases the pro-inflammatory cytokines to initiate immune response when infection commences, and on the other hand, exerts anti-inflammation when an infection persists.
Interestingly, Zhang et al.  reported on the combinational effects of oral polysaccharides like lentinan and tremellan on mice which were immunized with inactivated H1N1 influenza vaccine. The results showed that mice in the polysaccharides with vaccine groups had improved viral clearance. The immunized rat which were fed with lentinan and tremella recovered faster than the mice receiving only the vaccine after infection.
Some polysaccharides isolated from mushroom might possess an acidic or a neutral characteristic due to different types of glycosidic linkages. Some are bound to protein or peptide residues such as polysaccharide-protein/-peptide complexes. One example is the protein-bound polysaccharide K (PSK) from T. versicolor. PSK is very popular among the patients with gastrointestinal cancer (GIC) and they consume it with or without chemotherapy [43, 44]. Most recently, a network meta-analysis revealed that PSK combined with chemotherapy can increase the patient overall survival by 3–5 years . Another meta-analysis and systematic review study also showed that PSK can extend survival in lung cancer patients . As exemplified by PSK, in addition to the primary structure, a higher structure of polysaccharides, such as chain conformation, plays an important role in their antitumor activities.
Ganoderan represents an immunomodulatory polysaccharide from G. lucidium. It is an antioxidant polysaccharide that was shown to prevent and control cerebral arteriosclerosis by regulating the NADPH oxidizing enzyme expression . It was also shown to exert protective effects in rats with chronic glomerulonephritis . On the other hand, pleuran, which was extracted from P. ostreatus, was first reported to be formulated as a β-glucan-based cream. The pleuran-based cream was found to be effective in mild to severe atopic dermatitis . In fact, β-glucan-rich P. ostreatus was found to be a functional food as it demonstrated hypoglycemic effect in diabetic mice, and it is capable of improving hyperlipidemia in obese mice [50, 51].
According to Zhang et al. , schizophyllan is a nonionic, water-soluble homoglucan which possesses a β-(1→3)-linked backbone with single β-(1→6)-linked glucose side chains at approximately every third residue. Schizophyllan is probably one of the oldest β-glucan discovered from mushroom. Since the mushroom Schizophyllum commune is an efficient wood-degrading fungus, it can directly utilize woody substances like corn fibers for the production of schizophyllan [53, 54]. Besides serving as a potential prebiotic with immunomodulating properties , schizophyllan is now being developed for bulk biomaterial applications, such as in enhanced oil recovery and as a component of bio-lubricants [56, 57, 58].
Grifolan is a branched β-(1→3) glucan extracted from G. frondosa . The proposed mechanism by which grifolan exerts antitumor effect includes first the enhancement of immunity against the bearing tumors and secondly, a direct antitumor activity to induce the apoptosis of the tumor cells . Grifolan also can be used for the prevention of the oncogenesis by oral administration (cancer-preventing activity). D-fraction , on the other hand, is a protein-bound β-1,6 and β-1,3 glucan (proteoglucan) extracted from G. frondosa. D-fraction was reported for the first time in 2017 with the ability to act directly on mammary tumor cells .
Overall, mushroom polysaccharides exert their bioactivity mainly via immunomodulation . They help the host to adapt to various biological stresses and exert a nonspecific action on the host, supporting some or all of the major systems. Most importantly, mushroom polysaccharides are nontoxic and place no additional stress on the body. Therefore, they are regarded as “biological response modifiers” with the potential as prebiotic to safeguard our gut microbiome .
Triterpenes are highly oxidized lanostanes . Triterpenes are widely reported in Ganoderma species. Zhou et al.  had reviewed that triterpene is one of the main components responsible for the claimed therapeutic efficacy of Ganoderma. In fact, the potential of Ganoderma triterpenoids against various cancer targets had been well documented .
Srisurichan et a.  also reported three new lanostane-type triterpenoids which exhibited a varying degree of cytotoxicity against human cancer cells depending on the different side chains they contain. The triterpenoids were named as spiro-astraodoric acid (58) and astraodoric acids E (59) and F (60) (Fig. 10). Interestingly, compound 58 possesses a spirocyclic lanostane triterpenoid structure (Fig. 9). The authors suggested that the presence of an acetoxy group on a lanostane side chain increased the cytotoxicity of the lanostane triterpenoids.
Homer and Sperry  have recently reviewed on the isolation of mushroom-derived indole alkaloids, along with their associated biological activities. The alkaloid compounds can be found in different quantities based on mushroom species, their developmental stages, climatic conditions, and the availability of soluble nitrogen and phosphorous in the soil .
Psilocin (61), an indole alkaloid found in the genus Psilocybe, is considered a natural monophenol which exhibit various properties including toxicity, and even antioxidant and therapeutic action . It demonstrates bioactivity similar to other psychoactive tryptamines by inducing psychoactive effects like alternation of mood, ease of anxiety, and relief of depression . Its mode of action is believed to occur through serotonin, a monoamine that regulates numerous physiological responses including those in the central nervous system [93, 94]. Most recently, Lenz et al.  reported the identification of ω-N-methyl-4-hydroxytryptamine (norpsilocin , 63) (Fig. 11) from the carpophores of Psilocybe cubensis (Earle) Singer. Interestingly, norpsilocin has not been previously reported as a natural product. According to the authors, it is probably liberated from its 4-phosphate ester derivative, which is a known natural product baeocystin. However, no bioactivity was reported for norpsilocin yet.
A recent clinical trial has shown that psilocybin exerts a pharmacological action against depression with no serious or unexpected adverse events in the patients on trial . Subsequently, the authors reported on the possible mechanisms of the post-treatment brain effects of psilocybin and found out that decreased amygdala cerebral blood flow is likened with reduced depressive symptoms .
The basidiocarps of an nonedible but medicinal “bitter cap” mushroom, Cortinarius infractus (Pers.) Fr., also contained infractopicrin (67) and 10-hydroxyinfractopicrin (68) (Fig. 12) . The acetylcholinesterase-inhibiting activity of these compounds was comparable to that of galantamine, a drug used for the treatment of mild to moderate Alzheimer’s disease . Notably, the alkaloids present in C. infractus are responsible for the distinctive “bitterness” of this mushroom species [100, 101].
Boletus curtisii Berk., an edible mushroom which is yellow when young and turns brown when old, produces an interesting collection of sulfur-containing β-carboline derivatives, one of which is canthin-6-one (69) (Fig. 12) . This indole alkaloid which is responsible for the bright yellow pigmentation is also found in a variety of higher plants and possesses cytotoxic properties against leukemic cells . Other alkaloids from edible mushroom also include echinulin (70), a triprenylated tryptophan-based diketopiperazine from an aromatic mushroom, Lentinus strigellus Berk [104, 105].
The study of mushrooms is growing in popularity because of their attributed health benefits. The aforementioned bioactive molecules found in mushrooms, i.e., polysaccharides, glucans, triterpenes, and alkaloids, contribute greatly to their curative properties like anticancer, anti-inflammatory , antivirus, and even anti-Alzheimer’s disease. Indeed, edible and medicinal mushroom has huge demand as “whole functional food,” as well as developed as a healthcare product. Overall, the mechanisms of action of the bioactive compounds, which were discussed in this chapter, still elude scientific inquiry and scientists are still working towards unraveling the biochemical pathways leading to the curative effects.
We acknowledge the support of this work by the University of Malaya BKP grant (BK011-2017). This work was also supported by the University of Malaya High Impact Research MoE Grants, namely UM.C/625/1/HIR/MoE/SC/02 and UM.C/625/1/HIR/MOHE/ASH/01(H-23001-G000008).
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