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180
CHAPTER 8 ADDITIONAL MEDICINAL PROPERTIES
Synopsis
Extracts from many medicinal mushrooms have long been
used for a wide range of ailments in traditional Chinese
medicine. Modern scientific and medical studies are
increasingly supporting many of these health claims. The
main areas of medical studies include blood pressurelowering,
cholesterol lowering, liver protective, antifibrotic,
anti-inflammatory, anti-diabetic and anti-microbial activites.
While the role of medicinal mushrooms in immunomodular and anti-cancer
activities represents the dominating theme of this report, it is important to recognise
that many of these mushrooms also show other quite significant medical properties,
such as blood pressure- lowering, cholesterol lowering, liver protective, antifibrotic,
anti-inflammatory, anti-diabetic, anti-viral and other anti-microbial activities (Ooi and
Liu, 1999; Ooi; 2000, Wasser and Weis, 1999a, b, Hobbs, 1995; Gunde-Cimerman,
1999). Only a brief resume will be given here of the extensive additional medical
properties of certain medicinal mushrooms which have been supported by recent
scientific and medical studies.
Cardiovascular and hypercholesterolemia effects
A highly significant cause of death in most developed countries is coronary
artery disease. The main risk factors are hypercholesterolemia and
dyslipoproteinemia, disturbance in blood platelet binding, high blood pressure and
diabetes. Increased blood levels of total cholesterol, low density lipoprotein (LDO)
and very low density lipoprotein (VLDL) cholesterol as well as lowered levels of high
density lipoprotein (HDL) cholesterol have been identified as major risk factors in the
development of coronary artery disease (CAD)(Alberts et al., 1989). As much as
2/3rd of total body cholesterol in most individuals is of endogenous origin. Clinical
181
intervention studies have clearly demonstrated the therapeutic importance of
correcting hypercholesterolemia.
The initial steps in the prevention and treatment of CAD and
hypercholesterolemia is the modification of the nutritional regime with a diet low in
fats and saturated fatty acids and rich in crude fibres. Mushrooms in general, and
Pleurotus, Lentinus and Grifola in particular, because of their high fibre content,
sterols, proteins, microelements and a low calorific value, are almost ideal for diets
designed to prevent cardiovascular diseases as first suggested by Traditional
Chinese Medicine (Breene, 1990; Hobbs, 1995).
When diet control is not successful the next step is drug therapy. Early
attempts to identify inhibitors of cholesterol synthesis resulted in the development of
inhibitors that could affect stages in the biosynthetic pathway for cholesterol
formation. A major rate-limiting step in the pathway is at the level of the microsomal
enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase;
mevalonate NADP+ oxidoreductase [CoA acylating] EC 1.1.1.34). HMG-CoA
reductase occurs early in the biosynthetic pathway and is among the first committed
steps to cholesterol formation that catalyses the reductions of HMG-CoA into
mevalonate (Rodwell et al., 1976).
Mevinolin (lovastatin) produced commercially from the filamentous fungus
Aspergillus terreus was the first specific inhibitor of HMG-CoA reductase to receive
approval for the treatment of hypocholesteremia (Alberts et al., 1980). The genus
Pleurotus of the medicinal mushrooms has several species that produce mevinolin
(Gunde-Cimerman and Cimerman, 1995). P. ostreatus has been shown to produce
the highest amount of lovastatin in the fruit-body, especially in the lamellae or gills.
182
Mevinolin has been detected in submerged fermentation broth of P. saca and in the
surface fermentation broth of P. sapidus (Gunde-Cimerman et al., 1993).
The addition of 4% dried Pleurotus to a high cholesterol diet effectively
reduced cholesterol accumulation in the serum and liver of experimental rats
redistributing cholesterol in favour of HLDL, reduced production of VLDL and LDL
cholesterol, reduced cholesterol absorption and reduced HMG-CoA reductase
activity in the liver (Bobek et al., 1991). Limited clinical trials with 15-20g dried
Pleurotus supplement in the daily diet over a one-month period reduced
hypercholesterolemia in many but not all patients (Bobek et al., 1998). It has been
suggested that Pleurotus mushrooms could be recommended as a natural
cholesterol lowering substance within the human diet (Gunde-Cimerman, 1999).
Somewhat similar results have been achieved with Grifola frondosa and Auricularia
auricula (Ryong and Tertov, 1989).
Antilipemic effects of polysaccharides from Tremella fuciformis and T.
aurantia have been shown to lower plasma cholesterol levels (Sheng and Chen,
1989; Kiho et al., 2000), while an antihypercholesterolemic agent has been produced
from fruit bodies and mycelium of T. aurantai (Koichi and Takahiro, 1999).
It has long been recognised that eritadenine, a compound extracted from
Lentinus edodes is able to lower blood serum cholesterol (BSC). Eritadenine
reduces BSC in mice not by inhibition of cholesterol biosynthesis but by the
acceleration of the excretion of ingested cholesterol and its metabolic decomposition
(Susuki and Oshima, 1974). Various studies have shown that Lentinus mushrooms
can lower both blood pressure and free cholesterol in plasma, as well as accelerate
accumulation of lipids in the liver, by removing them from circulation (Kabir and
Kumura, 1989). It has been suggested that high dosages of eritadenime may impair
183
the secretion of very low-density lipoprotein cholesterol and in a similar manner to
soybean protein, eritadenine lowers cholesterol by decreasing the ratio of
phosphatidylcholine (PC) to phosphatidylethanolamine (PE) in liver microsomes
(Sugiyama and Yamakawa, 1996). Several small studies with Lentinus extracts in
Japan have shown positive decreases in serum cholesterol in young women and
people older than 60 years of age (Hobbs, 1995).
Nucleic acids from L. edodes also have significant platelet agglutinating
inhibitory effects (antithrombotic activity) (Hokama and Hokama, 1981). PSK also
causes decreases in LDL cholesterol in hyperlipidemia patients (Tsukagoshi 1984).
A recent review of literature by Francia et al. (1999) has collated how different
fungal activities can reduce the effects of risk factors for cardiovascular diseases in
experimental animals. Of the 17 species of macrofungi examined, including some
well recognised medicinal mushrooms, 16 showed at least one of the following
activities, i.e. ability to reduce hypercholesterolemia or to treat dyslipoproteinemia;
possibility to decrease arterial hypertension or hyperglycemia, and the ability to cure
disturbances in platelet aggregation (Tables 1-4). However, water extracts of
fruitbodies of L. edodes have been shown to lessen the effectiveness of blood
platelets in the process of coagulation and consequently those who bleed easily and
who take anticoagulants should exert caution when chronically consuming extracts
of L. edodes in therapeutic amounts or water-soluble fractions such as LEM (Yang
and Jong, 1989). Nevertheless, the exact mechanisms of action remains to be
elucidated before considering an eventual human treatment application for
prevention or cure of cardiovascular diseases. This review contains an extensive list
of relevant references.
184
References for Tables 1-4 can be found in Francia et al. (1999). Many of
these extracts have long been used in traditional Chinese medicine for treating
various cardiovascular disorders (Hobbs, 1995; Willard, 1990).
Table 1 Effects of macrofungi on lipids and cholesterol
[Seven fungi had an effect on lipids in general and cholesterol in particular]
1. Six species reduced total cholesterol level
Auricularia auricula – judae
Cordyceps sinensis: the activity could be due to a polysaccharide, the CSF30,
composed of galactose, glucose and mannose.
Ganoderma lucidum
Grifola frondosa
Pleurotus ostreatus
Tremella fuciformis
2.
Two species reduced the ‘bad cholesterol’ level
Auricularia auricula – judae
Tremella fuciformis
3.
Three species reduced the triglyceride level
Cordyceps sinensis
Grifola frondosa
Lentinus edodes
4.
Agaricus campestris: demonstrated no hypocholesterolemic activity.
Table 2 Macrofungi reducing blood platelet binding
[Six species reduced platelet binding (in vitro]
Auricularia auricula-judae
Calyptella sp: the active compound is the 5-hydroxy-3-vinyl-2 (5H) – furanone.
Ganoderma lucidum: the binding activity is due to adenosine.
Kuehneromyces sp: the active compound is kuehneromycine B.
Neolentinus adhaereus: the active compound is 2-methoxy-5-methyl-1,4
benzoquinone.
Panus sp: the activity is due to two compounds, panudial and nematolon.
185
Table 3 Macrofungi with an arterial blood pressure lowering effect
[Three fungal species reduced the arterial pressure]
Ganoderma lucidum
Grifola frondosa
Tricholoma mongolicum: the decrease of arterial pressure attributable to a
lectin.
Table 4 Macrofungi reducing glycemia
[Six species appeared to decrease glycemia]
1
Four species were active in insulin-dependent-diabetes.
Agaricus bisporus
Agrocybe aegerita: the glycemia lowering was due to two polysaccharides:
AG-HN1, a polysaccharide of high molecular weight composed of glucose
and AG-HN2, a polysaccharide of low molecular weight composed of
fructose, galactose, glucose and mannose.
Cordyceps sinensis: could be due to the CS-F30, a polysaccharide
composed of galactose, glucose and mannose.
Tremella aurantia: the active compound is the TAP (Tremella acidic
Polysaccharide).
2.
One species was active in non-insulin-dependent-diabetes.
Grifola frondosa: this mushroom is able to diminish glycemia but also
insulemia and the blood level of triglycerides.
3.
One species showed an activity only in non-diabetic animals.
Coprinus comatus.
Due to their high content of fibre and proteins and low fat content, extracts of
edible mushrooms have been considered to be ideal foods for dietetic prevention of
hyperglycemia (Gunde-Cimerman, 1999). Extracts of several medicinal mushrooms,
including Tremella aurantia, ‘Cordyceps sinensis’, Ganoderma lucidum and
Auricularia auricula-judae have been shown to lower blood glucose (Kiho et al.,
1995; Yan et al., 1998; Hikimo et al., 1989). The blood glucose and triglyceride (TG)
lowering effects of water soluble extracts from Lentinus edodes, Pleurotus ostreatus
and Phellinus linteus in the streptozotocin-induced diabetic model have been clearly
186
demonstrated (Kim et al., 1997, Kim et al., 2001). Such results strongly suggest that
these mushrooms have potential preventive and therapeutic action in diabetes
mellitus (type I and II).
Antimicrobial effects
Antimicrobial drugs have long been used for prophylactic and therapeutic
purposes. Unfortunately the recent increase in the occurrences of drug-resistant
bacterial strains is creating serious treatment problems. Consequently, the
antimicrobial activity of various antitumour polysaccharides from medicinal
mushrooms are being re-evaluated in terms of their clinical efficacy. Such
compounds would be expected to function by mobilising the body’s humoral
immunity to ward off viral, bacterial, fungal and protozoal infections resistant to
current antibiotics.
Many cancer and AIDS patients die of opportunistic infections because of
immunosuppression (Table 5). Several mushroom polysaccharides have shown
antiviral activity against ectromelia virus and cytomegalovirus infections (Jong and
Donovich, 1990). Lentinan from L. edodes when used in conjunction with
azidothymidine (AZT) suppressed the surface expression of HIV on T-cells more
than AZT did alone. Lentinan and sulphated lentinan exhibited a potent anti-HIV
activity resulting in inhibition of viral replication and cell fusion.
Lentinan has also shown: (a) antiviral activity in mice against VSV (vesicular
stomatis virus), encephalitis virus, Abelson virus, an adenovirus type 12; (b)
stimulated non-specific resistance against respiratory viral infection in mice; (c)
conferred complete protection against an LD75 challenge dose of virulent mouse
influenza A/SW15; (d) increased resistance to the protozoal parasites Schistosoma
japanicum, Sch. mansoni; (e) exhibited activity against Mycobacterium tuberculosis
187
bacilli resistant to antituberculosis drugs, Bacillus subtilis, Staphylococcus aureus,
Micrococcus lenteus, Candida albicans and Saccharomyces cerevisiae; (f)
increased host resistance to infections with potentially lethal Listeria monocytogenes
(for original references see Wasser and Weis, 1999a).
LEM and a new lignan-rich compound JLS-18 derived from LEM block the
release of infectious Herpes simplex virus in animals (Sarkar, 1993) and it has been
suggested because of its high activity that JLS-18 could be of value in the treatment
of hepatitis B and AIDS patients (Yamamoto, 1997).
Sulfated Schizophyllan polysaccharide displayed strong anti-HIV activity while
the anti-tumour effect was reduced or lost (Ito and Sugawara, 1990). Schizophyllan
has also been reported to enhance protection against Staphylococcus sp. infection
(Matsuyama et al., 1992).
The Japanese National Institute of Health and the US National Cancer
Institute have both stated that sulfated Grifola frondosa extract are able to prevent as
much as 97% HIV infected T-helper lymphocytes from being destroyed in vitro. This
is important because measuring the T-helper cell count makes it possible to trace the
progress of HIV to full blown AIDS (Ishikawa, 1991; US National Cancer Institute,
1992). Interestingly, G. frondosa, D-fraction together with dimethyl sulfoxide
(DMSO) has also shown success in treating AIDS associated Kaposi sarcoma
(Zhuang and Mizuno, 1999).
PSK has been shown to induce potent antimicrobial activity against
Escherichia coli, Listeria monocytogenes and Candida (Tsukagoshi, 1984; Sakagami
and Takeda, 1993).
In recent years Basidiomycetes and other higher fungi including some
recognised as medicinal mushrooms have been re-investigated as sources of novel
188
antibiotics – mainly as a result of the increasing difficulty and cost of isolating novel
bioactive compounds from the Actinomycetales such as Streptomyces.
Difficulties such as slow growth rate in fermenters of Basidiomycetes and the
low yield of products derived from them compared with the Actinomycetes are now
far outweighed by the opportunity of finding new antibiotics with novel structures
types as well as compounds with new modes of action (Brizuela and Garcia, 1998).
The fact that the Basidiomycetes have been insufficiently investigated coupled with
the broad range of structural types of antibiotics which are produced by these
organisms, suggests that they may well be a source of new and useful bioactive
compounds (Anke, 1989).
A recent extensive examination of over 200 species of Basidiomycetes in
Spain demonstrated that almost 50% had significant direct antibiotic activity against
a range of test organisms. It was interesting to note that the bracket polypore
Piptoporus betulinus carried by the historic Iceman (Chapter 2) displayed a high
broad spectrum antibiotic activity! (Suay and Arenal, 2000).
Researchers have shown that a water extract of L. edodes demonstrated
growth-enhancing effects on colon-inhabitating beneficial lactic acid bacteria,
Lactobacillus brevis and Bifidobacteria breve. The effective factor in the extract is
considered to be the disaccharide sugar, trehalose. The authors suggest that the L.
edodes extracts can improve the beneficial intestinal flora of the gut and reduce the
harmful effects of certain bacterial enzymes such as β-glucosidase, β-glucuronidase
and tryptophanase as well as reducing colon cancer formation (Bae, 1997).
Clearly, the antimicrobial potential of extracts of several types of medicinal
mushrooms and indeed other Basidiomycetes not yet exploited must warrant further
examination. The proven immuno-modulatory effects of many of these mushroom
189
species will be of significance especially when such infections occur in individuals
where the immune system is not functioning well such as young children, the elderly
and with patients enduring major anaesthetic and surgical procedures.
Table 5 Spectrum of mycoses and mycetes related to AIDS (Wasser and Weis,
1999a)
Mycoses Causative
organisms/saprophytes
Main target issues Incidence
%
Dermatophytoses
Anthropophillic dermatophytes:
Trichophyton rubum,
Epidermophyton floccosum, and
others
Skin and appendages
80-90
Candidoses
Candida albicans, C. tropicalis, C.
parapsilosis, C. guiliermondii, C.
krusci, and other species
Oral cavity; skin;
vagina; oesophagus
70-90
25-30
20-25
Torulopsidoses
Torulopsis glabrata, T. candida
Intestinal tract;
Parasitic;
Saprobic
1-2
70-90
Trichosporosis
Trichosporon cutaneum
Systemic, mainly brain <1
Cryptococcosis
Histoplasmosis
Cryptococcus neoformans
Brain (lungs, skin)
5-7
A series of studies has recently been carried out with a PGG-glucan on
patients undergoing high-risk major abdominal and thoracic surgery or high-risk
gastrointestinal surgery. PGG-glucan is a highly purified proprietary β-(1-3)-glucan
with β-1,6 branches (poly 1-6 glucotriosyl-β 1-3 glucopyranose glucan) (Onderdonk
et al., 1992). Three separate multicentre (including Harvard Medicial School),
randomised, placebo-controlled, double-blind clinical trials were carried out. In the
initial study patients receiving high doses of β-glucan (2.0 mg/kg) exhibited
significantly fewer postoperative infections complications when compared with
placebo (Babineau et al., 1994a). In a second study, patients given β-glucan had 1.4
infections per patient vs. 3.4 infections in the placebo group (Babineau et al., 1994b).
In a further study involving 1,249 patients the βb-glucan-treated patients showed a
190
statistically significant (39%) reduction in serious infections and death compared with
placebo (Dellinger et al., 1999). However, this final study was terminated before
anticipated completion because of an increased incidence of adverse effects in
patients receiving PGG-glucan. Since β-(1-3) glucans exhibit considerable structural
diversity such trials should be repeated with β-(1-3) glucans derived from the
medicinal mushrooms which have demonstrated no adverse human side-effects.
With the increasing concern of hospital-derived postoperative microbial infections
together with antibiotic resistance, such studies must warrant serious consideration,
and further expansion with mushroom-derived β-glucans must be considered
because of their proven antimicrobial effects.
Antioxidant , anti-inflammatory, free radical scavenging activities
and the ageing process
A wide variety of pathological damage, such as DNA, carcinogenesis and
cellular degeneration, related to the ageing process and ageing itself can be caused
by reactive oxygen species (ROS) produced by sunlight, ultraviolet and ionising
radiation, chemical reactions and metabolic processes. Furthermore, there is a vast
accumulation of studies that implicate oxygen derived free radicals such as
superoxide, hydroxyl radicals and high energy oxidants such as peroxy nitrite as
mediators of inflammation, shock and ischemia/reperfusion injury (Cuzzocrea et al.,
2001). There is also growing evidence to show that production of ROS at the site of
inflammation can contribute to tissue damage (Salvimini et al., 1996). Interventions
against ROS could exert beneficial effects on inflammation and shock (Halliwell and
Parihar, 1984). Several mushroom species have been studied for anti-inflammatory
and antioxidant activities (Ukai et al., 1983) and patents have been established for
these usages (Xiu, 1996).
191
Extracts of G. lucidum can apparently remove the hyperoxide radical believed
to be a main factor in the human ageing process (Liu et al., 1997), and the ageing
mouse model (Pan et al., 1999). In a clinical trial with 30 elderly people Ganoderma
lucidum extract (GLE) was given oral 1.5 g 3 times daily for 30 days. Interleukin-2
and interferon (IFN) production by peripheral mononuclear cells (PBMC) and NK cell
activity in vitro were respectively measured. Production of IL-2 and IFN were
significantly increased after GLE treatment. Such results could suggest that GLE is
a possible treatment to raise the cellular immunological activity in ageing people
(Tao and Feng, 1991; Tao, 1993).
A Ganoderma lucidum polysaccharide GLB7 decreased the production of
oxygen free radicals and antagonised the respiratory burst induced by PMA in
murine peritoneal macrophages (Li and Lei, 2000). Such observations could imply
that the polysaccharide-induced inhibition of oxygen free radicals in murine
peritoneal macrophages play an important role in the anti-ageing effect of
Ganoderma extracts.
PSK in a cell-free system consisting of hypoxanthine-xanthine oxidase rapidly
quenched the superoxide radical, a property not shared by Schizophyllan (Sakagami
and Aoko, 1991). PSK further repressed the mimetic activity of superoxide
dismutase (SOD) and promoted oxidative stress relief for cancer-bearing hosts
(Kobayashi and Kariya, 1994). PSK also gave protection to macrophages from
lipoperoxide accumulation and foam cell formation created by oxidatively modified
low-density lipoprotein (Yuan and Meiz, 1996). This protection is believed to be due
to the induction of gene expression of antioxidative enzymes (Chen and Zhou,1997).
PSP shows similar scavenging effects on superoxide and hydroxyl radicals (Hu and
Chen, 1992). Significant superoxide and hydroxyl radical scavenging activities have
192
been demonstrated for several mushroom antitumour polysaccharides (Liu et al.,
1997).
Hepatoprotective effects
Fruit-bodies of Ganoderma lucidum have long been a major factor in folk
medicine for the treatment of chronic hepatitis (Willard, 1990). Ganoderic acids R
and S were isolated from cultured mycelia and shown to have strong antihepatotoxic
activity in galactosamine-induced cytotoxic tests with primary cultured rat
hepatocytes (Hirotani and Ito, 1986). Another hepatoprotective compound,
ganosporeric acid A, was isolated from the ether-soluble fraction of the spores of G.
lucidum (Chen and Yu, 1991). The wide spectrum of medical efficacies of
Ganoderma lucidum, including hepatoprotective activities, is shown in Table 6.
A polysaccharide fraction from L. edodes showed liver protective action in
animals together with improved liver function and an enhance production of
antibodies to hepatitis B (Mizuno, 1995). Lentinan and LEM have given favourable
results in treating chronic persistent hepatitis and viral hepatitis B patients (Zhu,
1985; Amagase, 1987). Extracts of G. lucidum have shown good results in treating
hepatitis, particularly in cases without severe liver impairment (Yan, 1987). A clinical
study with lyophilised extract of G. lucidum showed highly beneficial results on
quality of life with patients suffering from active hepatitis B (Soo, 1994).
There have been other interesting medical reports relating to marked
improvement with patients suffering from cirrhosis of the liver and chronic hepatitis B
with extracts from Dendropolyprus umbellatus (Bensky and Barolet, 1990),
Schizophyllan commune (Kakuma, 1991), Trametes versicolor (Zhou, 1989), and
Poria cocos (Guo, 1984). PSP may, thus, be useful in the wider context of the
treatment of hepatitis (Yeung, 1995).
193
Table 6 Medical efficacies of Ganoderma lucidum (Kim and Kim, 1999)[see for
relevant references].
Efficacy
Compound
Anti-HIV activity Ganoderic acid α
Ganoderic acid β
Ganoderic acids B, C1, H
Ganoderiols A, B, F
Ganodermanondiol
Ganodermanontriol
Ganolucidic acid A
Lucidumol B
3β, 5α-Dihydroxy-6β-methoxyergosta-7-diene
Antihypertension (ACE inhibitor) Ganoderic acids B, D, F, H, K, S, Y
Ganoderol B
Bitterness Ganoderic acids A, C1, J
Lucidenic acids A, D1
Lucidone A, C
Cytotoxicity Ganonderic acids T, V, W, X, Y, Z
3β-Hydroxy-26-oxo-5α-lanosta-8,24-dien-11-one
Ergosta-7,22=diene-3β, 3α,9α-triol
Enzyme inhibitor
FPT inhibitiona Ganoderic acids A and C
PLA-2-inhibitionb Ganoderic acid T
DNA pol. β inhibitionc 5,8-Epidoxy-5α,8α-ergosta-6, 22E=dien-3β-ol
Hepatoprotective Ganoderic acids R, S
Ganosporeric acid A
Histamine release inhibition Cyclooctasulfur
Ganoderic acids C and D
Hypocholesterolemic Ganoderic acid Mf
Ganodermic acid B
Ganodermic acid T-O
Platelet aggregate inhibition Ganodermic acid S
aFPT : farnesyl protein transferase
bPLA2: phospholipase A2
cDNA pol: DNA polymerase
This Chapter has only been a brief overview of the many other aspects of
medical usage of the medicinal mushrooms which are being pursued worldwide. It,
hopefully, shows the direction of medical research into these compounds and their
undoubted value and significance in areas outwith cancer and immunotherapy.
194
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