The Use of Mushrooms in the Development of Functional Foods, Drugs, and Nutraceuticals: Functional Food Properties and Applications

Abstract

Mushrooms are becoming a vital component of the human diet for the prevention and treatment of various diseases. The use of mushrooms for developing functional foods, drugs, and nutraceuticals is reviewed in this chapter, with emphasis on present or potential medical implications. As functional foods, mushrooms represent a paradigm of integrating tradition and novelty, due to their wide spectrum of pharmacological properties. Their bioactive components can be extracted or concentrated as nutraceuticals, and/or a diverse class of dietary supplements. Functional foods and nutraceuticals, particularly mushrooms, are immunoceuticals with antitumor and immunomodulatory effects which target and modulate biological processes that foster the development of diseases. Several mushroom products, mainly polysaccharides such as &;#x003B2;&;#x02010;D&;#x02010;glucans, have proceeded successfully through clinical trials and are used as drugs to treat cancer and chronic diseases. In sum, the present status and future prospects open new avenues for upgrading mushroom species from functional food to translational mushroom medicine.

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Wild Plants, Mushrooms and Nuts: Functional
Food Properties and Applications
Edited by Isabel C. F. R. Ferreira, Patricia Morales, and Lillian Barros
Mountain Research Centre (CIMO), School of Agriculture, Polytechnic Institute of
Bragança, Portugal
Department of Nutrition and Bromatology II, Faculty of Pharmacy,
Complutense University of Madrid, Spain
Mountain Research Centre (CIMO), School of Agriculture, Polytechnic Institute of
Bragança, Portugal

This edition first published 2017
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Library of Congress Cataloging‐in‐Publication Data
Names: Ferreira, Isabel C. F. R., 1979– editor. | Barros, Lillian, editor. | Patricia Morales, editor.
Title: Wild plants, mushrooms and nuts : functional food properties and applications /
[edited by] Isabel Ferreira, Patricia Morales, Lillian Barros
Description: Chichester, UK ; Hoboken, NJ : John Wiley & Sons, 2017. |
Includes bibliographical references and index.
Identifiers: LCCN 2016036173 (print) | LCCN 2016045177 (ebook) | ISBN 9781118944622 (cloth) |
ISBN 9781118944639 (pdf ) | ISBN 9781118944646 (epub)
Subjects: LCSH: Functional foods. | Mushrooms. | Nuts. | Wild plants, Edible.
Classification: LCC QP144.F85 W54 2016 (print) | LCC QP144.F85 (ebook) | DDC 581.6/32–dc23
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Wild Plants, Mushrooms andNuts: Functional Food Properties andApplications, First Edition.
Edited by Isabel C. F. R. Ferreira, Patricia Morales, and Lillian Barros.
© 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd.
123
5
5.1 Introduction
It is so determined by Nature that right from the beginning everyone’s life, at least for a
certain period of time, depends on the strict fulfillment of Hippocrates’ advice: “Let
food be thy medicine and medicine be thy food” (Milner 2002). In this context, the use
of mushrooms to improve health represents an important cultural heritage as they have
been used since time immemorial as a source of highly tasty/nutritional foods and
medicinal preparations according to traditional ecological knowledge transmitted
through the generations by the greatest early civilizations (Pereira et al. 2012; Stamets
2002; Wasser 2010a; Wasser & Weis 1999). Sometimes the health benefits of their use
were so impressive that ancient people converted the result observed into long‐lived
stories of mushroom magic (Hobbs 2000). Thus, experiences of ethnomycological uses
of mushrooms deserve a modern evaluation.
Although for most people mushrooms are still considered as one of the curiosities of
Nature, by combining tradition and new information, edible and medicinal mushrooms
are now attracting more attention. Looking at the health‐related issues of the new mil-
lennium, the driving forces for this upsurge of interest in mushrooms include aging,
projections of the global burden of cancer and chronic noncommunicable diseases
(e.g. cardiovascular diseases, diabetes, obesity, and neurodegenerative disorders, among
others), with cancer being the main cause of death around the world in the last few
years, and pandemic diseases like acquired immune deficiency syndrome (AIDS).
Acost‐analysis carried out at Harvard University suggested that if current health trends
are not addressed, the costs to medical services associated to chronic nontransmissible
The Use ofMushrooms intheDevelopment ofFunctional
Foods, Drugs, andNutraceuticals
Humberto J. Morris1, Gabriel Llauradó1, Yaixa Beltrán1, Yamila Lebeque1,
RosaC. Bermúdez1, Nora García1, Isabelle Gaime‐Perraud2, and Serge Moukha3,4
1 Center for Studies on Industrial Biotechnology (CEBI), University of Oriente, Cuba
2 IMBE Biotechnologies et Bioremediation (IMBE‐EBB), Faculte St Jerome, France
3 Department of Toxicology, UFR des Sciences, Pharmaceutiques‐Université Bordeaux Segalen, France
4 INRA, UR1264, Mycologie et Sécurité des Aliments, BP81, 33883 Villenave d’Ornon, France

Wild Plants, Mushrooms andNuts
124124
diseases will rise to US$47 trillion in the next 20 years (Bloom et al. 2011). In conse-
quence, there is an increase in consumers’ interest in modifying lifestyles, particularly
through a health‐promoting and/or disease‐preventing diet (Chang & Wasser 2012;
Keservani et al. 2010; Mahabir & Pathak 2013; Shahidi 2012).
Mushrooms are emerging as a vital component of the human diet and several com-
prehensive reviews of their nutritional value have been presented (Chang & Buswell
2003; Kalač 2013; Khan & Tania 2012; Ulziijargal & Mau 2011) (see also Chapter3).
Thus, mushrooms have become attractive as a functional food and as a source of drugs
and nutraceuticals (Chang 2009; Ferreira et al. 2009; Patel et al. 2012) and world pro-
duction in 2012 was 30 million tons (Wasser 2014). Mushrooms as functional food and
nutraceuticals (dietary supplements) can help in the intervention of subhealth states
and may prevent the full‐blown consequences of life‐threatening diseases (Vikineswary &
Chang 2013).
Several mushroom species are known to possess medicinal value and some are already
being used for such purposes. Of the known mushroom species, approximately 700 are
considered to be safe with medicinal properties (Wasser 2010a). Pharmacological
effects have been demonstrated for many traditionally used mushrooms, including spe-
cies from genera Ganoderma, Lentinus (Lentinula), Agaricus, Auricularia, Flammulina,
Grifola, Hericium, Pleurotus, Trametes (Coriolus), Schizophyllum, Lactarius, Phellinus,
Cordyceps, Inonotus, Inocybe, Tremella, and Russula (Lindequist et al. 2005; Patel &
Goyal 2012; Stamets 2002; Vikineswary & Chang 2013). In this wonderful world,
Ganoderma, mushroom of immortality, has been considered as king of medicinal
mushrooms, followed by Lentinula and others, including Pleurotus (Patel et al. 2012).
Fruiting bodies as well as mushroom mycelia have a broad range of bioactive proper-
ties (see Chapter4). Mushrooms are thought to exert approximately 130 pharmacologi-
cal functions such as antitumor, immunomodulatory, antigenotoxic, antioxidant,
antiinflammatory, hypocholesterolemic, antihypertensive, antiplatelet‐aggregating,
antihyperglycemic, antimicrobial, and antiviral activities (Lindequist 2013; Patel et al.
2012; Paterson & Lima 2014). Many controlled studies have investigated this long list of
medicinal actions, thus upgrading mushrooms to today’s world of evidence‐based
medicine (Wasser 2014).
Mushrooms are natural bioreactors for the production of compounds with human
interest for biotechnological applications (Ferreira et al. 2010; Pereira et al. 2012).
Thebioactive molecules comprise high molecular weight compounds, mainly polysac-
charides, and low molecular weight secondary metabolites (de Silva et al. 2013).
Polysaccharides (especially β‐glucans) are the best known and most potent mushroom‐
derived substances, with antitumor and immunomodulatory effects, thus acting as
biological response modifiers (BRMs) by improving the host immune system (Chan
etal. 2009; Chen & Seviour 2007; Wasser 2002; Zhang et al. 2007). The vast structural
diversity of mycochemicals (phenolic compounds, terpenes, lactones, steroids, alka-
loids, among others) provides unique opportunities for discovering new drugs that
target and modulate molecular and biochemical signal transduction pathways (Chang &
Wasser 2012; Patel & Goyal 2012; Zaidman et al. 2005). Some species possess a variety
of bioactive compounds and therefore may be able to produce enhanced pharmaco-
logical effects. The best example is Ganoderma lucidum (Curtis) P. Karst., which
contains not only more than 120 different triterpenes but also polysaccharides, proteins
and other bioactive molecules (Wasser 2010b).

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 125
Owing to this plethora of useful bioactive compounds, mushrooms represent a grow-
ing segment of today’s pharmaceutical industry. Better insight into the different roles of
multiple active compounds and the mechanisms underlying their biological action will
accelerate commercial production of pharmaceuticals for therapeutic applications.
Asian countries have a head start in the study of medicinal mushrooms compared to the
rest of the world, and Western medicine still has a lot to learn from Eastern practices
(Paterson & Lima 2014). As presented later in this chapter, several immunoceutical
polysaccharides have been developed for clinical and commercial purposes in Japan,
Korea, and China. For instance, the Chinese pharmacopeia lists more than 100 mush-
room species for medicinal use, and fungal polysaccharide extracts have been used for
over three decades as an adjuvant to cancer radio‐ and chemotherapy (El Enshasy &
Hatti‐Kaul 2013; Kidd 2000; Martel et al. 2014).
Ongoing research projects are aiming to promote mushrooms as a new generation of
“biotherapeutics” (Patel & Goyal 2012). Given that only about 10% of mushroom biodi-
versity has been studied so far (see Chapter2), and few of them have been characterized
with regard to health benefits, it is likely that new active compounds will be discovered
in the future (Hawksworth 2012). Particularly in tropical areas, 22–55% (in some cases
up to 73%) of mushroom species have not yet been described (Bass & Richards 2011).
Medicinal mushroom science has been recognized as a successful multidisciplinary
new branch of science which has experienced great progress in the last 30 years. As a
consequence, around 400 clinical trials have been performed to evaluate the effects of
medicinal mushrooms in various diseases and more than 50 000 scientific studies and
15 000 patents on medicinal mushrooms have been produced so far (Wasser 2014).
This chapter will summarize the available information and reflect the present state of
mushroom use for developing functional foods, drugs, and nutraceuticals. These pros-
pects are expected to provide new avenues for upgrading mushrooms from functional
food to translational mushroom medicine.
5.2 A Window into the“Garden” ofaNovel
ClassofProducts
The Chinese have an ancient saying which highlights the concept that medicine and
food have a common origin. At the intersection between food, nutrition, and medicine
and encouraged by growing concerns about the impact of diet on health and efforts to
achieve “optimal nutrition,” a rich “garden” of terms has emerged, for many of which
there are no absolute definitions accepted by the scientific community. In this section,
we will try to open a window into this puzzle in order to provide a comprehensive
perspective on the contemporary uses of mushrooms in the context of this book.
Most mushroom‐derived preparations find use not as pharmaceuticals (“real” medi-
cines) but rather as a novel class of products with different names: food supplements,
tonics, functional foods, nutraceuticals, phytochemicals, mycochemicals, biochemo-
preventives, and designer foods (Chang 2009; Wasser & Akavia 2008). Our starting
point will be the functional foods and nutraceuticals, a growing field in food science
seeking alternatives to improve personal health and reduce healthcare costs. According
to the International Life Sciences Institute of North America (ILSI), functional foods
are “foods that by virtue of physiologically active food components consumed as part of

Wild Plants, Mushrooms andNuts
126126
the usual diet provide health benefits and/or reduce the risk of chronic diseases beyond
basic nutritional functions” (Coles 2013). Such foods range from traditional foods
possessing demonstrated physiological benefits as well as processed foods, e.g. forti-
fied with added or concentrated ingredients to functional levels (Betoret et al. 2011;
Prakash et al. 2014).
The term “nutraceutical” was coined from “nutrition” and “pharmaceutical” in 1989
by Dr Stephen DeFelice and is defined as “a food (or part of a food) that provides medi-
cal or health benefits, including the prevention and/or treatment of a disease.” Based on
this definition, a functional food would be a kind of nutraceutical (Keservani et al. 2010)
and in some countries the two terms are used interchangeably.
In the case of mushrooms, the terms “nutraceutical” and “functional food” are syn-
onymous (Chang & Buswell 1996, 2003). In the general context of this book, including
wild edible plants and nuts, we will discuss “mushroom nutraceuticals” in correspond-
ence with the Health Canada definition describing them as products isolated or purified
from foods generally sold in “pharmaceutical forms” of pills, capsules, and liquids, not
usually associated with food. A nutraceutical is demonstrated to have a physiological
benefit or provide protection against chronic disease (Mahabir & Pathak 2013). Thus,
nutraceuticals could be found in many products emerging as “dietary supplements,”
comprising ingredients obtained from food, plants, and mushrooms (fungi) that are
taken without further modification, separately from foods for their presumed health‐
enhancing benefits. Therefore, they may be classified as a category between foods
and drugs (Wasser & Akavia 2008).
“Phytochemicals” are specific types of nutraceuticals and comprise the naturally
occurring, biologically active compounds found in plants which have capabilities of
inhibiting various diseases, as part of the antioxidant defense molecules among other
physiological actions on the human body. Important phytochemicals are secondary
metabolites such as phenolic compounds, sterols, and alkaloids. Phrases like “chemo-
preventive agents” are sometimes used to describe phytochemicals thought to reduce
risk for certain types of cancer (Jabeen et al. 2014). Analogically, “mycochemicals” refers
to the untapped metabolites from mushroom fungi that can be used as nutraceuticals
and as new life‐saving drugs (Patel et al. 2012). Similar to “phytopharmaceuticals,” the
resulting drugs should be considered as “mushroom pharmaceuticals” (Lindequist 2013).
In the mushroom science community, the term “nutriceutical” is also an accepted
definition emerging from the recognition of numerous biological activities of mush-
room products. A “mushroom nutriceutical” is a refined/partially refined extract or
dried biomass from either the mycelium or fruiting body of a mushroom, which is
consumed in the form of capsules or tablets as a dietary supplement (DS) (not a food)
and has potential therapeutic applications (Chang & Buswell 1996, 2003; Chang &
Miles 2004). According to Wasser and Akavia (2008), mushroom‐based products
can serve as a diverse and superior class of dietary supplements. Regular intake of
medicinal mushroom preparations may enhance the immune response of the human
body, thereby increasing resistance to disease. Acting as immunopotentiators, these
mushroom preparations modify host biological responses and therefore, they are also
known as biological response modifiers (BRMs) (Chang 2009; Wasser 2014; Wasser &
Weis 1999). Moreover, several classes of mushroom bioactive substances having
immunotherapeutic efficacy when taken orally can be considered as immunoceuticals
(Kidd 2000; Petrova et al. 2005).

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 127
Although our garden seems like an intricate labyrinth, the truth is that edible and
medicinal mushrooms as well as mushroom products have definitively arrived (Chang&
Wasser 2012). The next questions are:
● How can humans use mushrooms as innovative resources for a healthy lifestyle and
in preventive and curative medicine?
● What defines a particular use?
● Are mushroom products “magic” like the foods of “Alice in Wonderland”?
5.3 Main Uses ofEdible Medicinal Mushrooms
intheAgeofHuman Health Crises
It is well known that we live in an age of human health crises. This is where the role
of edible and medicinal mushrooms with their products has become important
(Chang & Buswell 2003; Cheung 2008). Nowadays, interest in biotechnological
cultivation of basidiomycete mushrooms is related to the increasing demand for
mushroom‐based biotech products in the pharmaceutical, food, and cosmetic indus-
tries (Badalyan 2014). The physiological functions of mushrooms can be described by
the pyramid model suggested by Chang and Wasser (2012). In this model, human
health may be divided into three states: health, subhealth, and illness. Mushrooms
themselves can be used as a food to promote a healthy state; pure refined products
can be used as medicine for ill health, and crude extract products can be used as
dietary supplements (nutraceutical for our purpose) for a subhealthy state, as well
asfor both healthy and ill states.
Thus, mushrooms are not only food but are the raw material for development of
functional food and dietary supplements (nutraceuticals). Mushrooms as functional
food can help in the early intervention of subhealthy states and may prevent the conse-
quences of life‐threatening diseases. The ideal strategy is subhealthy intervention and
prevention rather than cure of chronic nontransmissible diseases by reverting to tradi-
tional knowledge as a source of chemopreventive food and nutraceuticals. Further, the
quality of life of those who are on lifelong therapeutic drugs may be enhanced by using
functional molecules from mushrooms (Vikineswary & Chang 2013). When used as
drugs, mushroom products can supplement other treatments and complement modern
medicine (Chang & Wasser 2012; Wasser 2014).
Between 80% and 85% of mushroom products are taken from fruit bodies either col-
lected in the wild or grown commercially, and the resulting products are considerably
diverse and unpredictable. Only 15% of all products are based on extracts from mycelia
and a small percentage are obtained from culture filtrates (Barros et al. 2007; Lindequist
et al. 2005). One main prerequisite to using mushrooms as drugs, nutraceuticals or for
other purposes is its continuous production in high amounts and at standardized qual-
ity. In addition, safety of mushrooms and their products should be verified and proven
as thoroughly as possible (Chang & Wasser 2012). In the opinion of Chang (2001),
mycelial products are the “wave of the future” because they ensure standardized quality
and year‐round production. Thus, submerged liquid fermentation can provide more
uniform and reproducible biomass and may provide valuable medicinal products
(Suárez & Nieto 2013). However, fruiting bodies obtained under good manufacturing

Wild Plants, Mushrooms andNuts
128128
practice (GMP) can also be used in the formulation of consistent and safe mushroom
products such as functional foods, nutraceuticals, and biologically active compounds
(Morris et al. 2014a).
As mentioned above, the range of human states in which mushroom‐derived prod-
ucts can be used is broad. Therefore, in this section, an attempt will be made to dissect
and distinguish the importance and uses of mushrooms as part of a modern healthy
lifestyle by passing from cuisine to clinical applications.
5.3.1 Mushrooms asFunctional Foods: AParadigm ofIntegrating
TraditionandNovelty
In agreement with the notion that prevention is better than cure, functional foods
based on medicinal mushrooms have gained popularity for their high nutritive and
medicinal values (Chang & Miles 2004; Mane et al. 2014; O’Neil et al. 2013).
Generally, edible mushrooms possess all three desired properties of food: nutrition
(seeChapter3), taste, and physiological functions (Chang & Buswell 2003; Chang &
Wasser 2012).
Over a 15‐year period (1997–2012), the global per capita consumption of mushrooms
increased from about 1 kg/year to over 4 kg/year, with Agaricus, Pleurotus, Lentinula,
Auricularia, and Flammulina, the so‐called “high five,” accounting for 85% of the world’s
mushroom supply (Royse 2014). Commercial cultivated mushrooms are readily available
fresh, frozen or canned and they are useful and versatile ingredients that can easily be
added to many dishes such as pizzas, casseroles, and salads (Stamets 2002). For example,
in Japan fresh and dried shiitake (Lentinus edodes (Berk) Singer) is used in medicinal
mushroom dishes– “Yakuzen.” These dishes can be prepared in many ways: boiled,
grilled, skewered, or on aluminum foil with different types of seasoning. Concentrates,
obtained from whole fruiting bodies or powdered mushrooms, are used as drinks
(Wasser 2010c). Mane et al. (2014) reported an improvement in nutritional quality and
therapeutic properties of meal items through the addition of fresh or fried oyster mush-
room Pleurotus sajor‐caju (Fr.) Singer without affecting its acceptability.
It is important to note the potential relevance of new species of culinary‐medicinal
mushrooms cultivated recently at commercial scale, e.g. Flammulina velutipes (Curt.:
Fr.) P. Karst., Tremella spp., Coprinus comatus (O.F.Mull.: Fr.) Pers., Hypsizygus spp.,
Dictyophora spp., and Hericium erinaceus (Bull.: Fr.) Pers. among others (Chang &
Wasser 2012). Wild mushrooms, for example, the nutritional and chemical (antioxi-
dant) inventory of Portuguese edible mushrooms in different habitats (Pereira et al.
2012), also deserve interest for the development of functional foods.
Several mushrooms are helpful in human ailments because they possess many typi-
cal pharmacological features, such as metabolic activation, bioregulation (maintenance
of homeostasis and immune balance), prevention/control of intoxication, decreasing
cholesterol levels, as antioxidants with rejuvenating and energy‐boosting properties,
and their role in the prevention and improvement of life‐threatening diseases such as
cancer, neurodegenerative disorders, diabetes, and metabolic syndrome (Lindequist
etal. 2005; Patel et al. 2012; Roupas et al. 2012). In view of these properties, mush-
rooms have been considered as “the new superfood” or “the choicest food of nutrition-
ists” (Mane et al. 2014).

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 129
Much more research is needed on the bioactive components in mushrooms to
determine their biological responses in humans. Promising evidence suggests that
ergothioneine, vitamin D, β‐glucan, and selenium offer positive effects for immune
function, intestine function, and weight management (Feeney et al. 2014). Information
about the proximate composition and energy as well as mushroom mycochemicals is
of great interest as both fruiting bodies and mycelia could be used as functional
foods and/or as a source of functional ingredients. Thus, the benefits of mushrooms
in human nutrition are growing as more research is undertaken to validate tradi-
tional claims.
5.3.1.1 Proven Functional Properties
Improvement of Digestive Function Mushrooms contain dietary fibers, including
β‐glucans, chitin, and heteropolysaccharides (pectinous substances, hemicelluloses,
polyuronides, etc.), as much as 10–50% in the dried matter (Wasser & Weis 1999).
Benefits of insoluble dietary fiber include reduction of bowel transit time, prevention of
constipation, and reduction in risk of colorectal cancer. Concerning soluble dietary
fibers and especially β‐(1,3),(1,6)‐D‐glucans, health benefits include lowering of blood
cholesterol, reducing hyperglycemia and hyperinsulinemia in relation to the control of
diabetes mellitus, reduction of risk factors for degenerative diseases such as cardiovascular
disease, cancer, hypertension, and promotion of the growth of beneficial gut microflora
(as a prebiotic) (Jacobs et al. 2009; Laroche & Michaud 2007).
Constipation is one of the most prevalent gastrointestinal complaints and high fiber
intake is recommended as an initial therapy. Ear mushrooms (Auricularia) are known
to have higher fiber content (by 50%) than other mushroom varieties. In patients
with functional constipation, fiber supplements using ear mushrooms have been shown
to significantly improve constipation‐related symptoms without serious side‐effects
(Kim et al. 2004).
Synytsya et al. (2009) reported that the fruit bodies of Pleurotus ostreatus (Jacq.:
Fr.) Kumm. and P. eryngii (DC.) Quél. contain significant amounts of β‐glucans,
which are components of both insoluble and soluble dietary fibers. The stems are a
better source of insoluble dietary fibers and glucans than the gastronomically attrac-
tive pilei, and therefore the stems can be used for the preparation of biologically
active polysaccharides utilizable as functional foods. Mushroom polysaccharides can
stimulate the growth of colon microorganisms, e.g. acting as prebiotics. Potential
prebiotic activity of glucan extracts L1 (water soluble) and L2 (alkali soluble) isolated
from stems of P. ostreatus and P. eryngii was tested using probiotic strains of
Lactobacillus, Bifidobacterium, and Enterococcus. These probiotics showed different
growth characteristics dependent on extract used and strain specificity. This exploi-
tation of fruit body extracts extends the use of P. ostreatus and P. eryngii for human
health.
Interactions between the host and its microbiota are increasingly recognized to be
critical for health. Rapid and reproducible changes in human gut microbiota were
evidenced in an interventional randomized clinical trial conducted with healthy volun-
teers treated for 14 days with a Trametes versicolor (L.: Fr.) Lloyd extract at doses of
1200 mg, three times daily (Beth Israel Deaconess Medical Center, NCT 01414010,
http://clinicaltrials.gov/ct2/results?term=mushroom).

Wild Plants, Mushrooms andNuts
130130
Antioxidant Properties Mushrooms packed with a wide array of bioactive components
are excellent antioxidants and antiinflammatory agents which may help to prevent the
occurrence and aid the treatment of chronic diseases including heart disease and
various cancers (Vikineswary & Chang 2013). Primary metabolites, including enzymes
such as glucose oxidase, superoxide dismutase, peroxidases, and laccases, may prevent
oxidative stress (Chang & Wasser 2012; Wasser 2010a). In addition, some common
widely consumed edible mushrooms have been found to possess antioxidant activity
(see Chapter4), which is well correlated with their total phenolic content. Phenolics
can act as free radical inhibitors (chain breakers), peroxide decomposers, metal
inactivators or oxygen scavengers and thus delay food spoilage and oxidative damage
in the human body (Asatiani et al. 2010).
The ability of preparations from Pleurotus ostreatus, Agaricus bisporus (J. Lge)
Imbach and Ganoderma lucidum (Curt.: Fr.) P. Karst to prevent oxidative damage of
DNA has been established (Jose et al. 2002).
Palacios et al. (2011) investigated the antioxidant properties of eight types of edible
mushrooms (Agaricus bisporus, Boletus edulis Bull., Calocybe gambosa (Fr.) Donk,
Cantharellus cibarius Fr., Craterellus cornucopioides (L.) Pers., Hygrophorus marzuolus,
Lactarius deliciosus (L.) Gray, and Pleurotus ostreatus). Homogentisic acid was the
freephenolic acid significantly present in all mushrooms although the content varied
considerably among the analyzed species. Flavonoids, such as myricetin and catechin,
were also detected in the mushrooms studied. The antioxidant properties were evalu-
ated bymonitoring linoleic acid autoxidation, and all the species showed inhibition,
with C.cibarius being the most effective (74% inhibition) and A. bisporus the species
with lowest antioxidant activity (10% inhibition).
The oyster mushroom, P. ostreatus, has potent antioxidant activity by virtue of its
scavenging hydroxyl and superoxide radicals, inhibiting lipid peroxidation, reducing
power on ferric ions, and chelating ferrous ions. P. ostreatus also exhibits good in vivo
antioxidant activity by reducing lipid peroxidation and enhancing the activities of
enzymatic and the levels of nonenzymatic antioxidants. The antioxidant principles
identified, such as ascorbic acid, α‐tocopherol, β‐carotene and flavonoid compounds
(rutin and chrysin), possibly contributed to the observed effects ( Jayakumar et al. 2011).
Phenolic compounds were detected in five extracts obtained from fruit bodies of
Pleurotus spp., obtained with solvents of different polarity; however, the highest levels
were found in polar extracts (water and ethanol) with values of 138.4 and 86.37 mg/100 g
dry base, respectively (Beltrán et al. 2013).
In addition to their total phenolic content, the antioxidant activity of mushrooms was
also found to be due to their polysaccharide content. Khan et al. (2014) evaluated the
antioxidant (lipid peroxidation inhibition) and functional (swelling power, fat binding,
foaming, and emulsifying properties) properties of β‐glucans extracted from edible
mushrooms A. bisporus, P. ostreatus, and Coprinus atramentarius (Bull.) Fr. The glucan
from C. atramentarius showed better antioxidant and functional properties com-
pared to those from A. bisporus and P. ostreatus. Fungal pigment melanin also pos-
sesses antioxidant, immune‐modulating, antimutagenic, and radioprotective properties
(Badalyan 2014).
Selenium has also received increasing attention as a possible cancer preventive
trace mineral, possibly through antioxidant protection and/or increased immune
function. Mushrooms accumulate selenium based on their growing medium and

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 131
provide more selenium than other foods in the fruit and vegetable group (Sadler
2003). Using the vacuum impregnation technique, Cortés et al. (2007) developed
a product with functional characteristics by means of fortification of P. ostreatus
mushroom with calcium, selenium, and ascorbic acid. Fortification levels for Ca
and Se of 7.3% and 42.3% of the Daily Recommended Intake (DRI)/100 g of fresh
mushroom, respectively, were obtained. At the beginning of storage at 4 °C, the
ascorbic acid content was 40% of the DRI/100 g of fresh mushroom. In another
study, Mao et al. (2014) purified and evaluated the antioxidant activities of sele-
nium‐containing proteins and polysaccharides in the Royal Sun mushroom,
Agaricus brasiliensis.
The antioxidant properties displayed by edible mushrooms as functional foods are
also closely associated with their antimutagenic, antigenotoxic, radioprotective, and
antiaging effects. Moreover, Naveen and Anilakumar (2014) reported that the antifa-
tigue property of A. bisporus was supported through decreased levels of lipid peroxida-
tion in tissue and also proposed the development of a fermented yogurt product using
an A. bisporus extract.
It is important to highlight that mushrooms are generally cooked or processed into
various culinary dishes industrially or at home. Cooking processes bring about a num-
ber of changes in their physical characteristics and chemical composition, including an
effect on antioxidant activity. Arora (2014) stated that, in general, frying does not affect
antioxidant activity but boiling and microwave cooking deplete the radical scavenging
ability of A. bisporus, Calocybe indica, Volvariella volvacea (Bull.: Fr.) Sing, Lentinula
edodes, and P. ostreatus.
Improvement ofBlood Lipid Profile and Lower Risk ofCardiovascular Disorders Mushrooms
may be able to improve cardiovascular disease risk through their ability to reduce blood
cholesterol levels. The results of numerous studies indicate that mushrooms are a
valuable source of statins (Endo 2004), which inhibit the activity of the key enzyme in
cholesterol synthesis, hydroxyl‐methyl‐glutaryl‐CoA reductase (HMG‐CoA reductase).
The best known edible higher basidiomycetes for potential production of lovastatin are
species of the genus Pleurotus and the highest content was found in the fruiting bodies
of P. ostreatus (Gunde‐Cimerman & Plemenitas 2001).
It is known that shiitake mushroom (L. edodes) is able to lower blood cholesterol and
lipids in animals and humans via a factor known as eritadenine (also called “lentinacin”
or “lentysine”). Apparently, eritadenine reduces serum cholesterol in mice, not by
inhibition of cholesterol biosynthesis but by acceleration of the excretion of ingested
cholesterol and its metabolic decomposition. For many patients (60 years of age or
older) with hyperlipidemia, consuming fresh shiitake mushroom (90 g/day for seven
days) led to a decrease in total cholesterol blood level by 9–12% and triglyceride level by
6–7% (Hobbs 2000). Although feeding studies with humans have indicated positive
effects, further research is needed.
In addition to the improvement in blood lipid profile, the cardioprotective role of
mushrooms is also related to their antithrombotic activity (antiaggregatory action on
blood platelets), including nucleic acid components of L. edodes (Kabir & Kimura
1989) and a blood pressure‐lowering effect (e.g. cardioactive proteins of V. volvaceae
(Yao et al. 1998) and antihypertensive angiotensin I‐converting enzyme inhibitory
peptides from Pleurotus cystidiosus O.K. Mill. and Pleurotus cornucopiae (Paulet)

Wild Plants, Mushrooms andNuts
132132
Rolland (Ching et al. 2011). A new glycoprotein (Fraction SX) obtained from Grifola
frondosa (Dicks.) Gray (Maitake) helps to maintain healthy cardiovascular function
(Zhuang & Wasser 2004).
In China, more than 40 patents use Tremella as the base for food products. It can
be made into a mushroom tea with the health‐promoting functions of nourishing
the kidneys, preventing coagulation, lowering blood pressure and prolonging life,
and is a multifunctional nutrient liquid that lowers fat and cholesterol levels in blood,
prevents cancer, and increases the number of leukocytes. A unique feature of
Tremella mushrooms is that its most often mentioned medicinal properties depend
on glucuronoxylomannans contained in fruiting bodies, or those produced in pure
culture conditions. Inparticular, the hypocholesterolemic actions may be attributa-
ble to the high molecular weight anionic charged polysaccharides, involving the
suppression of cholesterol absorption from the digestive tract (Reshetnikov et al.
2000). These bioactive materials may be beneficial for applications in the medicinal
food industry.
Improvement of Glucose Homeostasis and Antidiabetic Effect Some protective effects of
mushrooms as functional foods have been investigated, invitro and in vivo, while some
clinical trials have confirmed their therapeutic implications as an effective alternative
treatment for type 2 diabetes mellitus (Deepalakshmi & Mirunalini 2014). This effect
appears to be mediated via mushroom polysaccharides (possibly both α‐ and β‐glucans)
via a direct interaction with insulin receptors on target tissues, although this mechanism
remains to be confirmed (Roupas et al. 2012).
A randomized, double‐blinded, and placebo‐controlled clinical trial (n = 72) showed
that A. blazei Murill supplementation in combination with metformin and gliclazide
improved insulin resistance in these subjects. An increase in adiponectin concentration
after A. blazei extract consumption for 12 weeks may be the relevant mechanism (Hsu
et al. 2007).
Jayasuriya et al. (2012) reported that long‐term consumption of P. ostreatus and
P.cystidiosus as a functional food appears to be effective for glycemic control. The study
evaluated the effect of a suspension, made with powdered mushrooms, on the fasting
and postprandial serum glucose levels in healthy volunteers at a dose of 50 mg/kg body
weight, followed by a glucose load. Reductions in the fasting serum glucose levels for
P.ostreatus and P. cystidiosus groups were 6.1% and 6.4%, respectively and the post-
prandial glucose reductions were 16.4% and 12.1%. Antihyperglycemic activity was
demonstrated with a water‐soluble polysaccharide from P. citrinopileatus fermentation
broth. The polysaccharide was effective in lowering blood glucose levels in diabetic
rats (Hu et al. 2006). Additionally, the in vitro and in vivo antidiabetic activity of
Calocybe indica suggests its therapeutic potential for the prevention and control of
diabetes as an easily accessible source of a natural antidiabetic functional food (Rajeswari &
Krishnakumari 2013).
Other results indicated that Tremella mesenterica Schaeff. (fruiting bodies, sub-
merged culture biomass and tremellastin, an acidic glucuronoxylomannan polysaccha-
ride) might be developed as a potential oral hypoglycemic agent or functional food
fordiabetic patients and those with high risk for diabetes mellitus (Lo et al. 2006).
Tremella constitutes the major part of functional foods, having pronounced medicinal

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 133
properties, with existing patents for hyperglycemia suppressants in the form of food or
drink (Reshetnikov et al. 2000).
Mushroom β‐glucans, as soluble dietary fiber, have been gaining interest as a food
ingredient due to their beneficial role in maintaining blood sugar balance via blood sugar
lowering effects, elevation of plasma insulin levels, and the enhancement of cellular insu-
lin sensitivity; they also have been shown to help in dyslipidemia, obesity, and metabolic
syndrome (El Khoury et al. 2012). Research into mushroom antiobesity potential con-
ducted in men and women who were overweight or obese (n = 73) revealed a significant
loss in body weight, body mass index (BMI), and waist circumference during the six
months of the trial in those consuming the mushroom diet (substitution of 8oz (227 g)
of fresh mushrooms for 8 oz of meat three times/week) compared with baseline (Poddar
et al. 2013).
Enhancement ofImmune Function andLower Risk ofCertain Tumors Edible mushrooms with
functional properties have long been suggested to possess immunomodulatory effects
(Lindequist 2013; Wasser & Weis 1999). It was stated in theRi Yong Ben Cao (1620),
written by Wu‐Rui of the Ming dynasty, that “shiitake accelerates vital energy, wards off
hunger, cures colds, and defeats body fluid energy” (Wasser 2010c). Many of these
effects are related to the immune system and recent investigations have found evidence
of the health promotion abilities associated with mushroom consumption, including
antiviral, antibacterial, antifungal, and antiparasitic effects (Tejera et al. 2013).
Many, if not all, basidiomycete mushrooms contain biologically active polysaccha-
rides in fruit bodies, cultured mycelium, and culture broth. Polysaccharides are the
most potent mushroom‐derived substances with antitumor/immunomodulating
properties. These polysaccharides are of different chemical composition, with most
belonging to the group of β‐glucans having β‐(1,3) linkages in the main chain and addi-
tional β‐(1,6) branches needed for their antitumor action. Most of the clinical evidence
for immunomodulating and antitumor activities comes from the commercial polysac-
charides, such as lentinan (from L. edodes), PSK (krestin) (from Trametes versicolor),
and schizophyllan (from Schyzophyllum commune Fr.: Fr.) (Chang & Wasser 2012; El
Enshasy & Hatti‐Kaul 2013; Wasser 2002). The use of these mushroom polysaccha-
rides as drugs will be discussed in section 5.3.3, and in this section the benefits of
foodproducts based on whole mushrooms or foods supplemented with β‐glucans to
support our immune system will be the focus of attention.
Fungi β‐(1,3)‐glucans are traditionally part of the Japanese diet, in which whole mush-
rooms are eaten. The consumption of fresh mushrooms was found to increase
anti‐β‐glucan antibodies in the serum of humans; it was also suggested to provide better
defense against pathogenic fungi (Ishibashi et al. 2005). In addition, dietary intakes of
A.bisporus (fresh) and L. edodes (dried) mushrooms and green tea combine to reduce
the risk of breast cancer in Chinese women (Zhang et al. 2009). Although many patents
have been published claiming immunopotentiator effects of β‐glucans in functional
foods, in some cases β‐glucan is incorporated in such a low quantity that the real health
benefit is difficult to determine (Laroche & Michaud 2007).
Two types of hydrogels of β‐D‐glucan, pleuran (from P. ostreatus) and lentinan,
havebeen added to yogurts, natural, sweetened, flavored or with fruit, to increase their
bioactivity. The application of both hydrogels to yogurts had no negative influence on

Wild Plants, Mushrooms andNuts
134134
thesensory acceptability of the products and all samples maintained very good quality
during the whole storage period. The regular daily consumption of such dairy products
could contribute to the reduction of relapsing or chronic infectious as well as autoim-
mune and oncological diseases, especially in more risky age groups (children and older
people) (Hozová et al. 2004).
Wild edible BaChu mushroom (Helvella leucopus Pers.), grown in Xinjiang Province,
China, can be used in the treatment of leukocytopenia, and reduced immunity due to
chronic hepatitis and radiochemotherapy. It also has a preventive role for AIDS. BaChu
mushrooms are reported to enhance the phagocytosis ability of leukocytes, lymphocyte
conversion ratio, and antibody titer (Meng et al. 2005). BaChu mushroom crude poly-
saccharides have been used in a processing technology for obtaining a beverage mixed
with water and fresh juice. This juice recipe has more than 14 000 IU of vitamin A and
over three times the vitamin C content of an apple (Hou et al. 2008).
Bioactivity analyses present a possible direction for developing reliable functional
foods based on whole shiitake or food supplemented with isolated lentinan. The
consumption of L. edodes has been associated with the proliferation, activation, and
modification of memory and naive innate immune cell populations (Stanilka et al.
2013) and it modulates human immune function by altering cytokine secretion (Dai
et al. 2013).
Nanotechnology has shown great potential for improving the extraction effectiveness
of bioactive compounds in functional foods. For example, a new method was developed
for nanoparticle extraction of water‐soluble β‐glucans from mushrooms (sparan, the
β‐D‐glucan from Sparassis crispa (Wulfen) Fr., and phellian from Phellinus linteus
(Berk. & M.A. Curtis) Teng). This “nanoknife” method could be used in producing β‐
glucans for the food, cosmetics, and pharmaceutical industries (Park et al. 2009).
Nanotechnology applied to mushrooms also aims to enhance solubility, facilitate
controlled release, improve bioavailability, and protect bioactive compounds during
processing, storage, and distribution.
Neurogenerative Potential and Improvement of Neurodegenerative Diseases Studies have
shown that consumption of Hericium erinaceus (lion’s mane mushroom) isassociated
with neurite‐stimulating activity through the induction of nerve growth factor (NGF)
(in vitro and in vivo) by dilinoleoyl phosphatidylethanolamine (DLPE), hericenones
C–H, and erinacines A–I. Preliminary human trials with H. erinaceus derivatives
showed efficacy in patients with dementia in improving the Functional Independence
Measure (FIM) score or retarding disease progression (Kawagishi & Zhuang 2008),
while a double‐blind, parallel‐group, placebo‐controlled trial with oral administration
of H. erinaceus to 50–80‐year‐old Japanese men and women diagnosed with mild
cognitive impairment reported significantly increased cognitive function scores
compared to placebo during intake (Mori et al. 2009). Therefore, this mushroom has
great potential to be developed as a functional food or nutraceutical for boosting brain
and nerve health and for improvement of subhealth states related to aging and delaying
neurodegeneration.
In sum, the consumption of whole edible‐medicinal mushrooms or their bioactive
ingredients as functional foods is a beneficial practice for preserving health. However,
postlaunch monitoring is needed to establish whether functional foods are safe and
effective under customary conditions of use and to assess their influence on the

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 135
effectiveness of drugs and patient compliance (Coles 2013). The development of new
functional foods from mushrooms is increasingly challenging. It remains to be deter-
mined how often, how much and what species or mixture of species should be con-
sumed to bring about a desired biological response (Vikineswary & Chang 2013).
5.3.2 Mushroom Nutraceuticals
The nutraceutical revolution leads into a new era of medicine and health, in which the
food industry is expected to become a research‐oriented sector similar to the pharma-
ceutical industry (DeFelice 1995). Nowadays, different mushroom‐based healthcare
commercial biotech products with preventive and curative effects are available and
largely consumable in the world market as nutraceuticals (dietary supplements, DS).
The market for DS from mushrooms is growing and is currently valued at more than
US$18 billion (representing 10% of the general market for DS) and the demand for such
products is expected to increase (Wasser 2014). For example, Aloha Medicinals Inc.
(Carson City, NV), with a monthly production of 400 000 kg of finished product (equiv-
alent to 16 million bottles of dietary supplement) is considered the largest in the world
(www.alohamedicinals.com).
Numerous studies have shown that certain mushroom DSs are effective in both
preventing and treating subhealth status and specific life‐threatening diseases owing to
the synergistic action of bioactive molecules, when regularly consumed; even in high
dosages (over 150 g of fresh mushroom), they demonstrate very low toxicity. Many
mushrooms or mushroom preparations traditionally taken as treatments for specific
conditions are now often marketed for use as prophylactic agents (Badalyan 2014;
Chang & Wasser 2012).
Mushroom‐derived products are neither food (functional food) nor pharmaceuticals
(drugs), because the active ingredient of most products is not a single, chemically
defined compound as used in conventional drug treatments. Therefore, they may be
classified as a type of DS or traditional medicine, which is a category between food
and drugs (Chang & Wasser 2012). Each one is commercialized as a DS, specifying that
the purpose is not to treat, diagnose, cure or prevent any disease, and they have not
been evaluated by the FDA. The main types of mushroom DS products available on
the market today are:
● artificial cultivated fruit body powders, hot water or alcohol extracts of these, or the
same extract concentrates and their mixtures
● dried and pulverized preparations or the combined substrate, mycelium, and mush-
room primordial after inoculation of edible semisolid medium (usually grains)
● biomass or extracts from mycelium harvested from submerged liquid culture grown
in a bioreactor
● naturally grown, dried mushroom fruit bodies in the form of galenic formulations like
capsules or tablets
● spores and their extracts (Chang & Wasser 2012; Lindequist 2013; Llauradó et al.
2013; Morris et al. 2011; Wasser & Akavia 2008).
Data regarding the dosage to be used are controversial; the suggested dosages vary
widely due to various forms and formulations. Although the fresh form can be a valuable
dietary supplement, the quantities one would require for therapeutic doses are so great

Wild Plants, Mushrooms andNuts
136136
that its consumption could cause digestive upset. According to traditional Chinese
medicine, the standard dose of the mushroom dried fruiting bodies per day in different
forms (tablets, capsules, liquid extracts, etc.) must be equivalent to about 100–150 g of
fresh mushroom material. Numerous clinical trials have established that six capsules
(three capsules two times per day or two capsules three times per day), of 500–1000 mg
each (biomass or extracts), is the accepted dosage of mushroom preparations
(Wasser 2014).
We illustrate this with shiitake mushroom, which is prescribed in various forms.
Itmay be ingested as a sugar‐coated tablet, capsule, concentrate, powdered extract,
syrup, tea, or wine. Tablets are usually made from a dried water extract of the mycelia
or fruiting bodies because drying concentrates the lentinan and other active principles.
Standardized extracts are also available, and they are preferred because the amount of
lentinan present is certified and clearly stated on the bottle. The standard dose of the
dried fruiting body in tea or in mushroom dishes is given as 6–16 g, equivalent to
approximately 60–160 g of fresh fruiting bodies. The dosage, usually in the form of a 2g
tablet, is 2–4 tablets/day (Stamets 2002; Wasser 2010c).
A brief overview of mushroom nutraceutical products is provided in Table5.1.
We can conclude that the diversity of mushroom DSs with respect to composition/
formulation items (combination of components containing in biomass, extracts or iso-
lated fractions of different mushroom species in one preparation or only one species,
combination of mushroom substances with other herbal products or pure nutraceuti-
cals such as vitamins and minerals, etc.) is enormous. Most of these mushroom DSs
containing polysaccharides function as immunomodulators. The physiological consti-
tution of host defense mechanisms is improved, which restores homeostasis, thereby
enhancing resistance to disease and in some cases causing regression. For example,
products developed from biotechnologically cultivated mycelia of edible mushrooms
Hericium erinaceus and Tremella spp. in combination with other natural substances
possess antioxidant and immune‐stimulating activity, and regulate the level of blood
lipids and sugar (Khan et al. 2013; Standish et al. 2008).
In developing productive research programs for nutraceuticals, it is important to
build a hierarchy of evidence for individual supplements, including understanding the
essentials of product characterization (purity, active ingredients, and potential mecha-
nisms of action), basic clinical chemistry, and subsequent rigorous testing in the setting
of clinical studies. Multiple lines of investigation can then be coordinated for enhancing
the knowledge base on a product, with the goal of informing practitioners and the
public on safety and efficacy of DS use (Hopp & Meyers 2010). The growing DS indus-
try has prompted the need for international governance in establishing regulatory and
standard benchmarks for the expanding world market. The scientific validation of
mushroom products can help boost their credibility (Wasser & Akavia 2008).
Where should functional foods and nutraceuticals (FFN) be positioned in current
guidelines as treatments for lifestyle‐related diseases? FFN, similar to pharmaceutical
agents, contain bioactive substances that target and modulate biological processes
that foster the development of disease. FFN are likely to prove useful in both alleviat-
ing and preventing human diseases. Thus, the gap that currently exists between FFN
research and the medical community needs to be closed such that FFN can be imple-
mented into clinical guidelines for chronic nontransmissible diseases throughout all
stages of therapy.

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 137
Table5.1 Overview ofsome mushroom nutraceutical products andtheir health effects.
Product Content Observations
Aloha Medicinals Inc. (www.alohamedicinals.com)
Organic Cordyceps
sinensis™ (525 mg)
C. sinensis alohaensis hybrid strain
(US and international patents)
50/50 mixture of hybrid
Cordyceps and CS‐4 Cordyceps.
This product is often combined
with Agaricus blazei.
Tru‐Cordyceps™
Immune‐Assist™
Critical Care
Formula
(500–mg)
A. blazei: 58.5% β‐(1,3)‐(1,6)‐D‐
glucan; C. sinensis: 30% β‐glucan and
deoxiadenosine and other
nucleosides; G. frondosa: 28%
β‐glucan (fraction D); L. edodes: 40%
β‐glucan (lentinan) and α‐glucan
(KS‐2); C. versicolor: 40% β‐glucan
(including polysaccharides P and K);
G. lucidum: 40% β‐(1‐3)‐(1‐6)‐D‐
glucan and triterpenoids
This product has proven a
significant reduction of the
adverse effects induced by
radio‐ and chemotherapy in
clinical trials, including appetite
loss, nausea, low energy status,
among others.
Immune‐Assist 24/7
(500 mg)
A. blazei, C. sinensis, G. frondosa,
L.edodes, C. versicolor, G. lucidum
(similar to the former formulation)
plus hybrid Cordyceps and a green
tea‐derived substance
This formula has proven to be
useful in HIV/AIDS patients after
clinical trials
Dosage: 3 tabs/day with meals
GanoSuper™ Concentrated Reishi extracts. Made
from four different strains of
Reishi–Black, White, Red and Purple
A concentrated extract for people
who want a fully water‐soluble
form of Reishi for use in their
coffee or tea. It is manufactured
so as to make it fully water soluble
so opened capsules can be
dissolved directly into the coffee
or other hot drink
Levolar Forte™
(750 mg)
Extract of C. sinensis, CS4 (from
C.sinensis), fraction D of G. frondosa,
extract of Coprinus comatus,
full‐spectrum Cordyceps sinensis,
cinnamon extracts, and biotin
Specifically designed for
compensating the symptoms
ofdiabetes mellitus and fragile
Xsyndrome
Dosage: 4 tablets/day for 2 weeks
Pharmaceutical Mushrooms (www.nwbotanicals.org)
Eighth Element™
(500 or 600 mg)
Cordyceps sinensis Increase in cellular energy in
about 28.8%
Dosage: 2 capsules/day
Maitake
(500 mg)
Grifola frondosa
(contains a diversity of β‐glucans)
Potent immunomodulating effect.
It stimulates T cell production
and is recommended for
immunodeficiencies
(Continued )

Wild Plants, Mushrooms andNuts
138138
Purica‐Immune FX
(250 mg)
A. blazei, C. sinensis, G. frondosa,
L. edodes, C. versicolor,
G. lucidum, Nutricol™ (bioflavonoid
concentrate)
Rich in β‐glucans, potent
immunopotentiators, and
antioxidant bioflavonoids
Hep‐Assist
(500 mg)
Hot water extracts and ethanol
precipitates of L. edodes, A. blazei,
G.frondosa, C. versicolor, G. lucidum,
and two C. sinensis extracts (one from
mycelium and other from the culture
broth)
The concentrated mixture of 200
β‐glucans and nucleosides from 6
different species of mushrooms
turns this formula into a valuable
adjuvant product in the treatment
of hepatitis B and C
Zhejiang Fangge Pharmaceutical and Healthcare Products Co. Ltd. (http://mushroom.
en.alibaba.com)
China’s largest edible and medicinal mushroom processing enterprise. The company supplies
mushroom powders, extracts (polysaccharides), supplements, and finished products (capsules
and tea bags) from: Grifola frondosa; Lentinus edodes, Ganoderma lucidum; Agaricus blazei;
Cordyceps sinensis; Hericium erinaceus; Coriolus versicolor; Poria cocos; Polyporus umbellatus;
Pleurotus ostreatus; Flammulina velutipes; Coprinus comatus, Pleurotus citrinopileatus; Agrocybe
aegerita; Agaricus bisporus; Tremella fuciformis; Auricularia auricula; Marasmius androsaceus;
Phellinus igniarius; Phaeoporus obliquus;Antrodia cinamomea; Auricularia polytricha
FineCo. Ltd. (www.fineco.net)
Fine‐Agaricus® Gold Highly concentrated micropowder;
active ingredients, protein‐bound
polysaccharides (100% Agaricus
mushroom polysaccharides)
Effective against several cancers
by enhancing the immune system.
Ithas a powerful balancing effect
on many physiological functions
and has been effective for treating
chronic diseases
Fine‐Mesima P® Micropulverized powder of dried
Phellinus linteus mushroom. Contains
P. linteus polysaccharide 50%,
dextrin50%
Information not available
Mushroom Wisdom (www.mushroomwisdom.com/products.php)
Super Reishi Contains both hot water and alcohol
concentrated extracts to achieve the
maximum range of beneficial
constituents (β‐glucans and terpenes);
also enhanced with immune‐boosting
Maitake D‐Fraction®
Believed to balance and support
the body systems, including heart,
lung, liver, nerve, and brain
function Dosage: 4 tablets daily or
2 tablets twice a day
Breast‐Mate® Phellinus linteus PL‐Fraction™ 1000
mg; Maitake PSX‐Fraction®
containing 18% glycoprotein
SX‐fraction 160 mg; broccoli sprout
extract (4:1) 100 mg; green tea extract
(50% polyphenols) 100 mg; vitamin
D3 800 IU
PL‐Fraction™ possesses potent
activity in maintaining healthy
breast cells. Breast‐Mate® also
contains synergistic ingredients
(SX‐Fraction®, green tea extract,
broccoli extract)
Dosage: 4 tablets daily or 2 tablets
twice a day
Table5.1 (Continued)
Product Content Observations

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 139
By synthesizing the benefits of both food and medicine, nutraceuticals are expanding
into a wide range of areas, competing against such basic items as raw fruit and vegeta-
bles and, in some cases, cutting‐edge pharmaceuticals (DeFelice 1995).
5.3.3 Mushrooms asaSignificant Source ofDrugs: Lessons fromWasser’s
Discovery Pathway
According to current categories of botanical products, medicinal mushrooms can serve
as “botanical drugs” or “real drugs.” Botanical drugs are complex extracts to be used for
treatment of disease and they are clinically evaluated for safety and efficacy just like
conventional drugs, but this process can be expedited because of the history of safe
human use. Botanical drugs are highly but not completely characterized and are pro-
duced under the same strictly regulated conditions as conventional pharmaceuticals.
Drugs (prescription drugs or over‐the‐counter drugs) require the most rigorous testing,
including three phases of clinical testing, to ensure safety and efficacy, and close scru-
tiny by the FDA and/or EFSA (Chang & Wasser 2012).
Öztürk et al. (2014) reported on mushroom species which were studied for their
chemistry and biological activities in the last two decades. In general, the authors
covered 24 types of polysaccharides including β‐glucans and other complexes from
13 mushroom species; 259 terpenoid compounds including seven monoterpenes,
19sesquiterpenes, 54 diterpenes, and 179 triterpenes from 29 mushroom species;
59 steroid compounds from 10 mushroom species; 41 phenolic compounds from
Mushroom
Emperors™
A. blazei Murill fruiting body 120 mg;
C. sinensis mycelium powder 120 mg;
Hericium erinaceus fruiting body
120mg; G. frondosa fruiting body
120mg; L. edodes fruiting body
120mg; Tremella fuciformis fruiting
body 120 mg; Maitake TD‐Fraction®
(10% D‐fraction 40 mg); Maitake
PSX‐Fraction® (18% glycoprotein
SX‐fraction 40 mg; Lion’s Mane
Amycenone® (hericenones 0.5%,
amyloban 6%, 40 mg); P. linteus
extract PL‐Fraction™ 40 mg; Inonotus
obliquus extract 40 mg; C. versicolor
extract 40 mg; Poria cocos extract
40mg; G. lucidum double extract
40mg; vitamin C 80 mg
Mushroom Emperors™ brings
together 6 holistic mushroom
powders with 8 concentrated
extracts, including proprietary
extracts (D‐fraction, SX‐fraction,
and amycenone) to create a
synergistic blend to help promote
overall health and vitality
Direction for use: 4 tablets daily
or 2 tablets twice a day
Product 4life (www.tienda4life.mx/web/Productos.aspx)
Transfer Factor Plus®
Tri‐Factor® Formula
L. edodes, G. frondosa, Cordyceps,
β‐glucans, hexaphosphate inositol,
β‐sitosterol, and an extract of olive
leaves
Provides an optimal level of
immune support, i.e. the activity
of NK cells can be increased to
437%. Also benefits the
cardiovascular system
Table5.1 (Continued)
Product Content Observations

Wild Plants, Mushrooms andNuts
140140
13 mushroom species; and 42 alkaloid compounds from 13 species. Therefore, it is
important to develop a knowledge base for individual products, which will provide
direction for further clinical investigations.
What steps should we follow to discover a myco‐compound with potential as a drug?
Wasser (2010a) proposed the Drug Discovery Pathway, which was specially prepared
for the development of mushroom pharmaceuticals. This pathway includes nine steps:
● mushroom cultivation and biomass production
● biomass extraction
● screening of mushroom extracts
● effect of selected extracts on a target of interest
● chemical fractionation of selected extracts
● elucidation of active fractions (compounds), mechanism of action, and potency
● effect on animal models
● preclinical drug development
● clinical drug development.
Wasser’s Drug Discovery Pathway gives a step‐by‐step guide and each phase provides
recommendations for successful development of mushroom drugs, from the test tube
of a mushroom collection to final clinical applications. The pathway will also open new
avenues in this “central highway” because there are concerns to solve and questions to
answer. Future biotechnological development, the application of modern high‐tech
screening, the OMICs sciences such as genomics and proteomics, research on validated
animal models, and the accurate assessment of clinical values of the candidate drug are
directions for approval of mushroom products as drugs. Although Wasser’s Pathway is
valid for any mushroom drug candidate, in particular, it is intended to play a pivotal role
in discovering the potential of low molecular weight metabolites for their use as drugs,
i.e. targeting cancer.
Out of the huge diversity of activities, the most frequently sought for the majority of
mushrooms is antitumor/immunomodulating activity. Those compounds able to stim-
ulate the biological response of immune cells are being pursued for the treatment of
cancer, immunodeficiencies (i.e. to protect AIDS patients against opportunistic infec-
tions) or for immunosuppression following drug treatment or surgical procedures.
They are also sought for combined therapies with antibiotics and as adjuvants for
vaccines (Lull et al. 2005; Wasser 2014). Polysaccharides are the most potent mush-
room‐derived substances with antitumor/immunomodulating properties (El Enshasy &
Hatti‐Kaul 2013; Mizuno 1999; Wasser 2002). Mushroom polysaccharides occur mostly
as glucans, some of which are linked by β‐(1‐3),(1‐6) glycosidic bonds and α‐(1‐3)
glycosidic bonds, but many are true heteroglycans. Historically, hot water‐soluble
fractions (decoctions and essences) from medicinal mushrooms, i.e. mostly polysac-
charides, were used as medicine in the Far East (Hobbs 2000).
Polysaccharides demonstrating remarkable antitumor and immunomodulating
activity in vivo have been isolated from various species of mushrooms belonging to the
Auriculariales, Tremellales, Polyporales, Gasteromycetideae, and Agaricomycetideae.
The number of polysaccharides extracted from the fruiting body or cultured mycelium
of each species is strongly dependent on the method of fractionation used, but in
general, the total amount of polysaccharides is higher in fruiting bodies (Wasser 2002).
Inaddition to their immune regulation potential, polysaccharides are useful biologically

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 141
active ingredients for pharmaceutical use, such as for antiradiation, anti‐blood coagula-
tion, anti‐HIV, and hypoglycemic activities (Shenbhagaraman et al. 2012).
One of the first reports on antitumor activities of hot water extracts from fruiting
bodies of mushrooms belonging to the family Polyporaceae (Aphyllophoromycetideae)
and a few other families was published by Ikekawa et al. (1969), demonstrating a host‐
mediated effect against grafted cancer, such as sarcoma 180 in mice. After this, the first
three major drugs were developed and commercialized from medicinal mushrooms;
the three were polysaccharides, specifically β‐glucans (krestin (PSK) and polysaccha-
ride‐peptide (PSP)) from cultured mycelia of Trametes versicolor, lentinan from fruiting
bodies of Lentinus edodes, and schizophyllan (SPG, sonifilan, sizofiran) from liquid
cultured broth of Schizophyllum commune. In addition, more than 100 types of poly-
saccharides with biological activities have been isolated from the fruiting body and
mycelia of Ganoderma lucidum (e.g. ganoderan, GLPS) (Wasser 2010b). Among the
most studied mushroom polysaccharides in Japan, China, Korea, Russia, and the US
forimmunomodulating/antitumor activities, we can mention grifolan or GRN, D‐ and
MD‐fractions (from Grifola frondosa), PL (from Phellinus linteus), PG101 (from
Lentinus lepideus (Fr.) Fr.), CA1 β‐glucan fraction and SCG (from Sparassis crispa), and
befungin (from Inonotus obliquus Pers. (Fr.) Boud. et Sing.) (Chen & Seviour 2007; Kidd
2000; Lull et al. 2005; Zhang et al. 2011).
Mushroom polysaccharides are among the emerging new agents that could directly
support or enhance immunotherapy, and their safety in use is important in biomedical
science. More than 50 mushroom species have yielded potential immunoceuticals
that exhibit anticancer activity in vitro or in animal models and of these, only a few have
been investigated in human cancers. The β‐D‐glucans or β‐D‐glucans linked to proteins
are currently the most promising class of immunoceuticals, displaying stronger immu-
noenhancing activity than the corresponding free glucans (Kidd 2000; Petrova et al.
2005; Vannucci et al. 2013; Wasser 2014).
A number of mushroom immunoceuticals polysaccharides have proceeded through
phase I, II, and III clinical trials. Lentinan (L. edodes), PSK and PSP (T. versicolor) have
been used in clinical trials with hundreds of cancer patients (stomach, colorectal,
esophageal, lung, breast, nasopharyngeal, and leukemia). Other compounds have only
been assessed with a relatively small number of patients and in many cases, the stand-
ards of these trials may not meet the current Western regulatory requirements, although
significant improvements in quality of life and survival of patients are reported (Paterson
& Lima 2014). A number of Chinese patents on the medicinal application of lentinan
administered orally (Sun & Wei 2007) or intravenously (Ma & Wang 2007) have been
published. The effect of lentinan in prolonging life has been observed, especially in
those with gastric and colorectal carcinoma, and this polysaccharide has been approved
for clinical use in Japan for many years and is manufactured by several pharmaceutical
companies (Zhang et al. 2011). Schizophyllan has also exerted beneficial activity for
patients with head and neck cancers, recurrent gastric cancer, stage 2 cervical cancer,
and advanced cervical carcinoma (Hobbs 2000).
PSK and PSP from T. versicolor have controlled various carcinomas in human clinical
trials. In Japanese trials undertaken since 1970, PSK significantly extended survival at
five years or beyond in stomach, colorectal, esophagus, nasopharyngeal, and lung
(nonsmall cell types) cancers, and in a HLA B40‐positive breast cancer subset. PSP
was subjected to phase II and III trials in China. It significantly improved quality of

Wild Plants, Mushrooms andNuts
142142
life and enhanced immune status in 70–97% of patients with stomach, esophagus,
lung, ovary, and cervix cancers. PSK and PSP boosted immune cell production, ame-
liorated chemotherapy symptoms, and enhanced tumor infiltration by dendritic and
cytotoxic Tcells. Their high tolerability, proven benefits to survival and quality of life,
and compatibility with chemotherapy and radiation therapy make them well suited for
cancer management regimens (Kidd 2000).
In clinical studies, G. lucidum products have been widely used as a single agent or in
combination with other herbal medicines or chemotherapeutic drugs, mainly in Asian
countries. However, randomized, placebo‐controlled and multicenter clinical studies
using G. lucidum alone have rarely been reported. In one randomized, placebo‐
controlled clinical study, 143 patients with advanced previously treated cancer were
given an oral G. lucidum polysaccharide extract (Ganopoly) of 1800 mg three times
daily for 12 weeks. The prostate‐specific antigen (PSA) levels in the five prostate cancer
patients were reduced significantly, indicating that Ganopoly may have an adjunct role
in the treatment of patients with advanced cancer although objective responses were
not observed (Gao et al. 2002). A polysaccharide injection formulated from G. lucidum
has been also developed (Jiang et al. 2014).
Although the maitake D‐fraction is a relatively new compound, the claims of benefit
are encouraging. There are a number of clinical trials in breast, prostate, lung, liver, and
gastric cancers under way in the US and Japan, and several US physicians have reported
good results with maitake D‐fraction. Grifolan‐D accomplished (>95%) cell death of
prostate cancer cells in vivo and hindered metastatic progress, increased NK cell activity,
and maintained the elevated levels of cytotoxicity for more than one year (Kodama
etal. 2003).
Much recent research has been carried out on Pleurotus spp. crude extracts and
isolated compounds such as polysaccharides, proteins, and other substances that
possess antitumor and immunostimulatory activities (Gregori et al. 2007). Antitumor
effects have been shown on different human tumor cell lines. From these results,
POPS‐1, a water‐soluble polysaccharide from the fruiting bodies of P. ostreatus, has
been considered as a potential candidate for developing a novel low‐toxicity antitu-
mor agent (Tong et al. 2009). A hot water mycelial extract from Pleurotus spp. (76.8%
polysaccharides) exerted in vitro antiproliferative activity against human NB4 leuke-
mia cells through apoptosis induction and cell cycle arrest in the G2/M phase (Morris
et al. 2014b). In light of its effects on macrophage phagocytosis and the hematopoiesis
response of mice that would otherwise remain damaged by radiation and chemo-
therapy substances, this extract could be considered as a candidate for radio‐ and
chemoprotective therapy (Llauradó et al. 2015; Morris et al. 2003). Used as an immu-
noceutical, Pleurotus fruiting body powder (55% polysaccharides) given orally for
seven days (1000 mg/kg) to cyclophosphamide‐treated mice potentiated the cellular
immune response and the lymphoproliferative‐stimulating index (Llauradó et al.
2013). Thus, Pleurotus‐based products could be promising for clinical immunotherapy
applications.
There are plenty of clinical studies proving the cancer inhibitory effects of other
mushrooms such as Inonotus obliquus, Phellinus linteus, Flammulina velutipes,
Cordyceps sinensis (Berk.) Sacc., etc (Wasser 2014). For example, studies conducted for
antitumor activities at the National Cancer Center (Japan) demonstrated that extracts
containing polysaccharides and glycoproteins prepared from Hypsizygus marmoreus

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 143
and F. velutipes showed positive effects on the cachexia of advanced cancer patients.
These extracts had better effects than methyl‐acetoxy‐progesterone in clinical response,
performance status, and quality of life (Ikekawa 2005). Befungin (a multi‐compound
preparation containing 50% of β‐(1‐3),(1‐6) glucans, terpenes, phenols, steroids, organic
acids, and microelements) obtained from Inonotus obliquus was approved as an antitu-
mor drug in Russia and reportedly successful in treating breast, lung, cervical, and
stomach cancers (Badalyan 2014).
Mushroom immunoceuticals act primarily by augmenting all the key pathways of
host immunity, both innate and adaptive, and signaling cascades. Due to a high poten-
tial for structural variability, polysaccharides have the necessary flexibility to affect the
precise regulatory mechanisms of various cell–cell interactions (Wasser & Weis 1999).
The antitumor action of polysaccharides requires an intact T cell component; their
activity is mediated through a thymus‐dependent immune mechanism. They activate
cytotoxic macrophages, monocytes, neutrophils, natural killer (NK) cells, dendritic
cells (DCs), B cells, and chemical messengers (cytokines, such as interleukins, inter-
ferons, and colony‐stimulating factors) that trigger complement and acute‐phase
responses. Also, mushroom polysaccharides induce gene expression of various immu-
nomodulatory cytokines and cytokine receptors (Lull et al. 2005; El Enshasy & Hatti‐
Kaul 2013; Zhang et al. 2007). The first step of action of these metabolites is their
recognition by certain receptors located on different immune cells and activation of
signal transduction pathways. It has been clarified that several β‐glucan receptors
mediate these activities, such as complement receptor 3 (CR3, αM β2‐integrin,
CD11b/CD18), lactosylceramide, glycosphingolipid, scavenger receptors, dectin‐1,
TLR‐2, and TLR‐4 (Brown et al. 2007; Li et al. 2011; Moradali et al. 2007).
In sum, a new class of antitumor and immunomodulating medicinal mushroom drugs
(the biological response modifiers (BRMs)) is emerging in the clinical scene. The appli-
cation of BRMs as a special type of immunotherapy to target and eliminate cancer
cells could represent a new kind of cancer treatment together with surgery, chemo-
therapy, and radiotherapy (Mizuno 1999; Wasser 2002, 2014). Findings suggest that
some mushrooms work in synergy with commercial anticancer drugs as an effective
tool for treating drug‐resistant cancers. Antitumor monoclonal antibodies in conjunc-
tion with β‐glucans have been considered as a novel anticancer immunotherapy against
GD2 ganglioside, G250 protein, and CD20 protein, respectively in experimental neuro-
blastoma, carcinoma, and CD20+ lymphoma (Vannucci et al. 2013; Xiang et al. 2012).
Mushroom β‐glucans might also have synergistic effects with monoclonal antibodies
used in cancer treatment similar to yeast β‐glucans.
More than 30 mushroom extracts and fungal compounds are currently being investi-
gated in clinical trials by the National Institutes of Health in the US. Table5.2 lists some
of these clinical trials with mushroom polysaccharides or polysaccharide‐rich extracts/
powders. The addition of new areas of application, apart from the immunological use
in oncology, opens interesting perspectives and makes the study of β‐D‐glucans a
prospective field of research. For example, β‐D‐glucans also appear suitable for use
innanomedicine for preparation of nanocarriers for drug or biological molecule deliv-
ery (Soto et al. 2012).
In addition to high molecular weight polysaccharides, another anticipated application
of mushroom species is concerned with the active pool of secondary metabolites with low
molecular weight (phenolic acids, flavonoids, terpenoids, lactones, quinones, steroids,

Wild Plants, Mushrooms andNuts
144144
Table5.2 Selection ofrecent clinical trials conducted withpolysaccharide‐rich mushroom‐derived
preparations.
Official title Intervention Subjects Purpose
Immune Benefits from
Mushroom Consumption
(University of Florida/
Mushroom Council)
Last updated: December 2, 2013
Dietary
supplement: 3 or
6 ounces (around
28 g) daily for
4weeks
52 healthy
patients
To determine whether
consuming shiitake
polysaccharide‐rich
mushroom is effective
in enhancing the
function of γ δ T cells
A Translational Breast Cancer
Prevention Trial of Mushroom
Powder in Postmenopausal
Breast Cancer Survivors (City of
Hope Medical Center/National
Cancer Institute) (NCI)
Last updated: June 5, 2014
Drug: white
button
mushroom
extract
Dose escalation
beginning at 5 g/
day, then 8, 10 up
to 13 g/day
16 females with
breast cancer, 21
years and older
To show that a whole
food extract of white
button mushrooms can
inhibit aromatase‐
induced estrogen
biosynthesis in women
who are breast cancer
survivors
Does Maitake Mushroom
Extract Enhance Hematopoiesis
in Myelodysplastic Patients? A
Phase II Trial (Memorial
Sloan‐Kettering Cancer Center/
Yukiguni Company)
Last updated: September 3, 2014
Patients will
receive maitake
mushroom
extract orally
3mg/kg twice
daily for
3months
43
myelodysplastic
patients, age 18
or older
To see whether maitake
improves the
hematopoietic response,
in particular, neutrophil
count and function, in
myelodysplastic patients
Efficacy and Safety of
Cauliflower Mushroom Extract
on Promotion of Immunity
(Chonbuk National University
Hospital)
Last updated: November 26,
2012
Phase II and III
Dietary
supplement:
cauliflower
mushroom
extract (1 g/day),
for 12 weeks
60 males and
females, 30 years
to 65 years
To evaluate the efficacy
and safety of cauliflower
mushroom extract on
promotion of immunity
(IL‐10, IFN‐ γ, TNF‐α,
and blood cell counts)
Phase Ib of Mushroom Powder
in Biochemically Recurrent
Prostate Cancer (City of Hope
Medical Center/National Cancer
Institute) (NCI)
Last updated: October 9, 2014
Drug: white
button
mushroom
extract. Dosages:
4, 6, 8, 10, 12,
and 14 g/day
36 male patients To study the side‐effects
and best dose of white
button mushroom
extract in treating
patients with recurrent
prostate cancer after
local therapy
A Randomized, Parallel,
Double‐blind, Placebo‐
controlled, Pilot Clinical Study
on the Effects of Yunzhi as
Dietary Supplement in 60 Adult
Patients Undergoing Adjuvant/
Neoadjuvant Chemotherapy for
Breast Cancer
(Hospital Clinic of Barcelona)
Last updated: December 14, 2010
Dietary
supplement:
Yunzhi extract
from
Coriolus
versicolor
3.5 g/day
60 women
patients with
diagnosis of
breast cancer,
18years and
older
To assess the effects of
the traditional Yunzhi
mushroom, as adjuvant
in the treatment of
patients with breast
cancer

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 145
and alkaloids) that have antitumor, antimicrobial, and antiviral properties. The scientific
investigation of these compounds has gained momentum in recent years because they are
simpler chemically and equivalent to existing fungal‐based pharmaceuticals, such as
penicillin and cephalosporins (Patel & Goyal 2012; Paterson & Lima 2014).
Mushroom terpenoids (tri‐ and sesquiterpenes) have cytotoxic, antibacterial, anti-
fungal, hypocholesterolemic, hypoglycemic, hypotensive, and antioxidant effects
(Badalyan 2014). About 400 bioactive molecules have been isolated from Ganoderma
species: G. lucidum, G. applanatum (Pers.) Pat., and G. tsugae Murrill. Among them,
lanostane‐type triterpenoids are promising candidates for the development of anti-
tumor drugs (Fatmawati et al. 2013). Ganoderic acids, ganoderenic acids, ganodermic
acids, applanoxidic acids, ganoderals, ganoderols, lucidone, ganodermanontriol, and
ganodermanondiol are some of the basidiomycetous triterpenoids. In spite of the fact
that many triterpenoids have been discovered in mushrooms, few studies have been
done to elucidate the mode of action of their anticancer and immunomodulating
effects. The research performed on G. lucidum has shown that such triterpenoids
could activate the NF‐kB pathway and modulate Ras/Erk, c‐myc, CREB protein, and
mitogen‐activated protein kinases, leading to other immune activations against tumor
cells (Calviño et al. 2010; Moradali et al. 2007; Petrova et al. 2008).
Hispolon, an active phenolic compound extracted from Phellinus spp., is known to
possess potent antineoplastic properties and to potentiate the cytotoxicity of chemo-
therapeutic agents. Hispolon induces epidermoid and gastric cancer cell apoptosis and,
regardless of p53 status, it inhibited breast and bladder cancer cell growth. Aa crucial
role of hispolon in ubiquitination and downregulation of MDM2 (the protooncogene
inhibiting the tumor suppressor function of p53) was reported, suggesting this phenolic
compound as an attractive therapeutic strategy in breast, gastric, and bladder cancers
(Chen et al. 2008; Lu et al. 2009).
As for low molecular weight mushroom compounds, only a minute fraction have
proceeded to a higher level of clinical evaluation. In this group, irofulven (6‐hydroxy-
methylacylfulvene), a novel synthetic antitumor agent derived from the sesquiterpene
illudin S of Omphalotus olearius (DC.) Singer, has been one of the most extensively
studied. Phase II clinical trials were performed in different tumors (advanced mela-
noma, advanced renal cell carcinoma, metastatic colorectal cancer, and recurrent or
Official title Intervention Subjects Purpose
Use of the Medicinal Mushroom
Agaricus blazei Murill in
Addition to High Dose
Chemotherapy in Patients With
Multiple Myeloma (Ullevaal
University Hospital)
Last updated: February 22, 2014
Phase II
Intake of 60 mL
A. blazei daily in
addition to
chemotherapy.
Commercial
name:
AndoSan™
39 patients
scheduled to
undergo
high‐dose
chemotherapy
with autologous
stem cell
support for
multiple
myeloma
To assess the effects of
Agaricus extract
(AndoSan™) in addition
to chemotherapy on
cytokine levels as well as
treatment response and
quality of life of patients
with multiple myeloma
Adapted from: http://clinicaltrials.gov/ct2/results?term=mushroom
Table 5.2 (Continued)

Wild Plants, Mushrooms andNuts
146146
persistent endometrial carcinoma), but unfortunately irofulven demonstrated minimal
to no significant antitumor activity in these trials (Zaidman et al. 2005). There are still
ongoing phase II clinical trials by MGI Pharma in recurrent ovarian cancer, hormone‐
refractory prostate cancer, and recurrent malignant glioma (http://adisinsight.springer.
com/drugs/800006987; Sborov et al. 2015).
As mentioned above, low molecular weight mushroom metabolites exhibit an
extraordinary diversity but their investigation in clinical trials and use as drugs is
currently scarce. Table5.3 presents an overview of some compounds whose pharmaco-
logical activities have been tested at the preclinical level, in some cases with contradic-
tory results depending on the model used, sample concentration, etc. Overall, in vivo
activity studies are limited when compared with in vitro studies. The compound quan-
tity of natural products might be one reason for screening biological activities in vivo.
Efforts should be made to find new sources for anticancer drugs using low molecular
weight mushroom metabolites that can inhibit or trigger specific responses, i.e. activat-
ing or inhibiting NF‐κB, inhibiting protein and especially tyrosine kinases, aromatase
and sulfatase, matrix metalloproteinases, cyclo‐oxygenases, DNA topoisomerases and
DNA polymerase, antiangiogenic substances, etc. (Chang & Wasser 2012; Patel & Goyal
2012; Petrova et al. 2008; Zaidman et al. 2005).
The available information about bioactive molecules of medicinal mushrooms sug-
gests that these may be powerful sources from which to develop novel pharmaceutical
products. It is hoped that as technology advances for the production of mushroom
drugs, there will be increased clinical research to ensure their safety and efficacy, thus
validating many claims made for the medicinal use of these products. As Chang and
Miles (2004) stated, “Anecdotal accounts are interesting and may be useful, but scientific
experimentation is essential.”
5.4 Conclusion
There is no better time for mushroom products to emerge as judged by their positive
impact on human quality of life. Recent basic and applied studies in mushroom metabo-
lism, biotechnology, and clinical trials represent a large contribution to the expansion of
mushroom potentialities for the development of functional foods, nutraceuticals, and
novel drugs.
Mushroom functional foods represent an opportunity to obtain innovative products
that would help to satisfy the demand that already exists. In addition, different mush-
room formulations provide health‐enhancing nutraceuticals for healthy and subhealthy
people. Although not “magic” products like those of “Alice in Wonderland,” based on
the multiple biological properties of mushroom nutraceuticals, the view of Stephen
DeFelice that “One good nutraceutical can wipe out the drugs” has gained momentum
in recent years.
However, many of the bioactive properties attributed to mushroom functional foods
and nutraceuticals are based on data obtained from in vitro and animal experiments
(Vikineswary & Chang 2013). Well‐designed and ‐conducted clinical trials and better
insight into the mechanism underlying the biological action of mushrooms will acceler-
ate commercial production of myco‐pharmaceuticals. A more detailed chemical and
biological characterization of both high and low molecular weight biologically active

Table5.3 Overview ofthepharmacological activity ofsome low molecular weight compounds frommushrooms invarious in vitro/in vivo systems.
Mycochemical
family Examples of compounds Mushroom Pharmacological effect
Terpenoids Irofulven (illudin’s
derivative)1,6,8 Omphalotus
illudens
Suillus placidus
Antitumor activity against human pancreatic carcinoma cell lines in vitro and in vivo, HT‐29
and HCT‐116 colorectal and A2780 ovarian carcinoma cells, head and neck, nonsmall cell
lung, malignant glioma, colon, ovary and prostate cancer. Phase II clinical trials are ongoing
Triterpene‐enriched fraction
WEES‐G6 (especially
ganoderic acid F)1,7
Ganoderma
lucidum
–
–
–
–
Selective growth inhibition of Huh‐7 human hepatoma cells. It caused a rapid decrease of
PKC and the activation of JNK and p38 MAPK protein kinase signaling pathways. Inhibition
of angiogenesis in an in vivo model
7‐oxo‐ganoderic acid Z and
15‐hydroxy‐ganoderic acid S
Inhibition activity against HMG‐CoA reductase and acyl CoA acyltransferase.
Ganoderic acid C21,3,7 Apoptosis induction in NB4 human leukemia cells. Effective against cell proliferation and colony
formation in MCF‐7 human breast adenocarcinoma cell line; mediated G1 cell cycle arrest
Ganoderic acid X1,7 Inhibition of DNA synthesis in human hepatoma cell lines (Huh‐7), inhibition of
topoisomerase I and Iiα, activation of apoptosis and inhibition of protein kinases
Lucidenic acid B1, 7 Implicated in the inhibition of Erk on HepG‐2 human liver cells, apoptosis
Tricholomalides A, B and C1, 7 Tricholoma spp. Induction of neurite outgrowth in rat PC‐12 cells
Sarcodonin G7Sarcodon scabrosus Suppression of inflammation induced by TPA, activation of caspases‐3 and ‐9 and increased
Bax/Bcl‐2 ratio, antiproliferative activity against HOC‐21, HEC‐1, U251‐SP, MM‐1CB, and
HMV‐1 human cancer cell lines.
Eryngiolide A7Pleurotus eryngii Cytotoxic effects against Hela and HepG2 tumor lines by using MTT assay
Steroids Ergosterol and ergosterol
peroxide6‐8 Multiple species Increase serum 25(OH) vitamin D2 levels (in vivo–humans). Antibreast cancer. Direct
inhibition of angiogenesis induced by solid tumors. Inhibition of leukemic cells proliferation
Blazein6,8 Agaricus blazei Induction of apoptotic chromatin condensation in human lung cancer cells and stomach
cancer cells
Ergosta‐4,6,8(14),22‐
tetraen‐3‐one (ergone)5Russula
cyanoxantha
Cytotoxic and antiproliferative activity towards HepG2 cells through apoptosis induction
and G2/M cell cycle arrest
(Continued )

Mycochemical
family Examples of compounds Mushroom Pharmacological effect
Nucleotide‐
derivatives
Cordycepin2,4‐6,8 Cordyceps militaris Inhibition of human leukemia cell growth by inducing apoptosis through a signaling cascade
involving a ROS‐mediated caspase pathway. It continues to be a potentially useful tool to
identify therapeutic targets
Clitocine6.8 Leucopaxillus
giganteus
It targets Mcl‐1 to induce drug‐resistant human cancer cell apoptosis in vitro and tumor
growth inhibition in vivo
Phenolic
compounds
Hispolon5,7 Phellinus spp. Inhibition of breast and bladder cancer cell growth, potentiation of cytotoxicity of
chemotherapeutic agents used in the clinical management of gastric cancer
Caffeic acid phenethyl ester
(CAPE)1,2,4 Agaricus bisporus,
Lentinus edodes,
Phellinus linteus,
Marasmius oreades
Specific cytotoxicity against tumor cells, shows NF‐κB inhibitor activity, and can be a
candidate for antitumor drugs, especially against breast cancer
Genistein (an isoflavone)1Flammulina
velutipes
Modulates G2/M checkpoint and apoptosis induction and suppresses proliferation of p53
null human prostate carcinoma cells. Inhibition of several tyrosine kinases and
topoisomerases. Also acts as antioxidant
Alkaloids Norsesquiterpene alkaloid7Flammulina
velutipes
Cytotoxicity against human cervical carcinoma KB cells in vitro by using the MTT assay
Isohericenone, isohericerin
and erinacerin A6‐8 Hericium
erinaceum
Cytotoxic activity against HCT‐15, SK‐MEL‐2, SK‐OV‐3, and A549
Sinensine7Ganoderma sinense Biological activity in protecting H2O2 oxidation‐induced injury on human umbilical vein
endothelial cells
Lactones Clavilactones A, B and D
(respectively CA, CB and CD)
and two semisynthetic
derivatives (diacetyl‐CA and
dimethyl‐CA)1
Clitocybe clavipes Inhibitory activity in kinase assays against the Ret/ptc1 and epidermal growth factor
receptor (EGF‐R) tyrosine kinases, weak inhibition activity when administered to mice
bearing the ascitic A431 tumor
Sources: Zaidman et al. (2005)1; Petrova et al. (2008)2; Calviño et al. (2011)3; Chang & Wasser (2012)4; Patel & Goyal (2012)5; Roupas et al. (2012)6; Öztürk et al. (2014)7; Paterson &
Lima (2014).8
MAPK, mitogen‐activated protein kinase; MTT, (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐ diphenyltetrazolium bromide; NF‐κB, nuclear factor κB; PKC, protein kinase C; ROS, reactive
oxygen species; TPA, 12‐O‐tetradecanoylphorbol 13‐acetate.
Table5.3 (Continued)

The Use ofMushrooms intheDevelopment ofFunctional Foods, Drugs, andNutraceuticals 149
compounds from different mushroom species appears necessary to better define the
rationale for their application in anticancer therapies as well as in other pathologies.
Glucan and proteoglycan immunoceuticals acting as biological response modifiers are
effective immune boosters for individuals afflicted with cancer or impaired immunity
and possess a unique clinical versatility. Interest in the investigation of new and pow-
erful low molecular weight compounds has increased due to the wide range of their
medicinal activities.
The target for the future should be to adopt regulations, standards, and practices from
Western and Eastern medicine that have proven to be the most valuable in the quest for
health benefits (Wasser 2014). Further sustainable research on the natural and genetic
resources of edible and medicinal mushrooms using improved screening methods of
OMICs sciences will assist future usage of their bioactive myco‐compounds to develop
unique health biotech products with a positive impact on human welfare. In sum, this
chapter provides insights into the possible uses of mushrooms as functional foods, nutra-
ceuticals, and drugs. The present status and future prospects suggest great potential for
upgrading mushroom species from functional food to translational mushroom medicine.
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