11.1 Introduction
According to the World Health Organization (WHO) report in the year 2010, the mortality rate due to coronary illness, cancers, diabetes, and obesity contributes to about 69% of the total 17.5 million recorded deaths worldwide. Cardiovascular diseases (CVD) are seen as the major contributor to the prevalence of high mortality rate in conditions such as diabetes, hypertension, aging, etc. Therefore, a large part of scientific infrastructure and resources are being utilized on cardiac research. The American Heart Association recommended to various authorities more than a 38.3 billion budget to pursue cardiac research and development during the financial year 2016.
Consumption of naturally available food and food products has long been advocated for healthy well-being. According to the International Life Science Institute, Europe, “A food can be regarded as functional if it is satisfactorily demonstrated to affect beneficially one or more target functions in the body, beyond adequate nutritional effects, in a way that is relevant to either an improved state of health and well-being and/or reduction of risk of disease” (Roberfroid 2002).
Mushrooms are functional foods with a large number of beneficial bioactive metabolites providing various physiological effects (Abdullah et al. 2012; VanderMolen et al. 2017). Over the years, incorporation of mushrooms, for example, Lentinus edodes, Agaricus bisporus, and Pleurotus spp., in the diet has turned out to be prevalent worldwide (Ferreira et al. 2009; Patel and Goyal 2012; Witkowska et al. 2011). The consumption of mushrooms translates to incorporating a supply of high-fiber, low-fat substance with low unsaturated fats and low amount of sodium along with biologically active phytochemicals such as phenolics; sterols, for example, ergosterol and chitosan; triterpenes; etc. The focus of this chapter will be primarily on those mushrooms used traditionally to treat CVD that have some evidence to warrant clinical evaluations. Mushrooms provide high nutritional value to the diet and delivers proven beneficial effects over obesity, diabetes, and cardiovascular diseases (CVD) (Inoue et al. 2013; Rao et al. 2010; Weng and Yen 2010; Zhou et al. 2009). Therefore, mushrooms are considered as a promising source of naturally occurring therapeutics consequent of which enormous focus is laid on understanding the pharmaceutical action and value of both edible and wild mushrooms (Wu et al. 2010b).
Mushrooms have long been an integral part of various traditional medicines. Hot water extracts of the fruiting bodies of mushrooms are considered to possess the medicinal properties (Boh et al. 2007; Chen et al. 2016). Cardiac diseases are a leading cause of death across the world. They have a multifactorial etiology arising from various functional disorders like hypertension, metabolic syndromes (diabetes, obesity), drug toxicity, aging, hypercholesterolemia, oxidative stress, etc. (Hobbs 2004). Various mushrooms that correspond to amelioration of such aetiological factors of CVD have been identified and their principle active metabolites explored in detail. Mushrooms such as Lentinus edodes, Auricularia polytricha, Flammulina velutipes, Pleurotus ostreatus, and Agaricus bisporus are proven hypocholesterolemic agents. Moreover, several mushrooms like Pleurotus pulmonarius and Leucopaxillus tricolor have also exhibited antihypertensive and blood pressure-lowering effects. Mushrooms with antioxidant and anti-inflammatory properties are appropriate agents that potentially provide protection to heart.
In the same line, mushrooms and their products that beneficially influence renin-angiotensin system, hdl cholesterol, apolipoprotein E, lipoproteins, lipoxidation end products, inflammatory cytokines, and chemokines are also largely considered for their therapeutic value (Ji et al. 1995). Most of these mushroom-based medicines have not been thoroughly investigated, and valuable scientific or clinical data supporting their therapeutic effects are scarce. With this approach of treating CVDs, a few mushrooms are considered as suitable dietary supplements with potential therapeutic value, viz., Chaga (Inonotus obliquus), Lion’s Mane (Hericium erinaceus), Maitake (Grifola frondosa), Coriolus (Trametes versicolor), Cordyceps (Cordyceps sinensis), Agaricus blazei (Agaricus subrufescens), Reishi mushroom (Ganoderma lucidum), Shiitake (Lentinula edodes), and Agarikon (Laricifomes officinalis) (Chien et al. 2016; da Costa et al. 2015; Nguyen et al. 2017; Sturm et al. 2016; Wang et al. 2017). Further knowledge on the bioactive constituents are very essential in providing needed resources to fortify mushroom nutrigenomics and pharmacogenomics fields which would help in making the right judgment for the medicinal application of mushrooms.
11.2 Pathophysiology of CVD
Cardiomyocytes are highly differentiated matured cells, and they cease to multiply soon after birth of an individual; therefore, event of hyperplasia is not common although recent studies suggest the possibility of cardiomyocyte proliferation in adult heart in exceptional cases. Meanwhile it is well known that cardiomyocytes in the heart undergo adverse hypertrophy and cell death due to changes such as hemodynamic overload (hypertension) or in pathological conditions like chronic inflammation, oxidative stress, hyperglycemia, and hyperlipidemia. The apoptosis of cardiomyocytes and subsequent fibrosis in the heart affect the cardiac contractile function which may lead to heart failure.
Hypertension is a common pathological condition affecting heart and with an epidemic proportion affecting 15–20% of all adults with disorders such as arteriosclerosis, stroke, and myocardial infarction. The renin-angiotensin system (RAS) plays a major role in regulating blood pressure and a critical role in the pathophysiology of cardiovascular diseases including congestive heart failure and hypertension (De Mello and Danser 2000). Renin produces angiotensin-I from angiotensinogen that is cleaved by angiotensin I-converting enzyme (ACE) to form angiotensin II which is a potent vasoconstrictor. Increase in angiotensin II is associated with hypertension and cardiovascular damages. Therefore, inhibition of ACE activity yield major antihypertensive benefits.
11.3 Properties of Mushrooms in Defense Against CVDs
11.3.1 Antiatherosclerotic Effects
Atherosclerosis is a progressive disease condition associated with increasing accumulation of lipids and fibrous elements in the large blood vessels and is a major risk factor for CVD. In this respect, various edible mushrooms and their mechanisms of actions responsible for the antiatherosclerotic effect have been widely studied. Inflammation and oxidative stress are important critical phenomena causing pathological cardiac events associated with atherosclerosis. Many edible mushrooms are known anti-inflammatory dietary agents, and several active ingredients from mushrooms have been isolated for their anti-inflammatory effects (Barros et al. 2007; Ganeshpurkar et al. 2011). These mushrooms are ideal candidates to treat cardiovascular disorders (Ganeshpurkar et al. 2011). Grifola frondosa, Hypsizygus marmoreus, and Pleurotus florida are some of the potential mushrooms that exert anti-inflammatory effects. Also, Agrocybe aegerita, Boletus edulis, Flammulina velutipes, and Pleurotus citrinopileatus are some of the mushrooms having antioxidants with antiatherosclerotic properties.
11.3.2 Antioxidative Effects
Dietary intake of antioxidants is an effective strategy to counter the onset of various CVD conditions. Polysaccharides and phenolic compounds of mushrooms possess strong antioxidative properties. They effectively neutralize radical elements by enhancing the activity of oxidative enzymes such as catalase, glutathione peroxidase, and superoxide dismutase and by stabilizing glutathione and malondialdehyde levels (Kozarski et al. 2015; Witkowska et al. 2011). Ganoderma lucidum, G. tsugae, Termitomyces heimii, T. mummiformis, Lentinula edodes, and Coriolus versicolor are mushrooms known for their antioxidant properties. Modification of LDL by oxidation is one of the critical causes of atherogenesis. The antioxidant activity on lipid peroxidation of various commercial mushrooms including L. edodes, F. velutipes, P. ostreatus, and V. volvacea have been correlated with the phenolic contents. In a clinical study, supplementing lyophilized powder of P. ostreatus to patients with dyslipidemia resulted in the increased activity of the antioxidant glutathione peroxidase demonstrating the efficient antioxidant effect of dietary intake of mushrooms (Kajaba et al. 2008).
11.3.3 Antihypertensive Effects
Hypertension or elevated blood pressure causes great stress and leads to adverse changes in the heart function. As mushrooms contain low concentration of sodium and high levels of potassium (182–395 mg/100 g), they are suitable dietary supplements to prevent hypertension effects. Various investigations reveal the antihypertensive effects of mushrooms such as Lentinula edodes, Ganoderma lucidum, Pleurotus narbonensis, and Grifola frondosa (Kabir et al. 1987; Lee et al. 2012). Mushrooms display diverse mechanism in providing antihypertensive effects (Table 11.1); however, ACE inhibition (Table 11.2) is one of the well-known effects of mushroom that contribute to cardioprotection from hypertension.
Table 11.1
Antihypertensive mode of action and biocomponents from edible mushrooms
Component | Mode of action | Source |
|---|---|---|
Tripeptide 3,3,5,5-tetramethyl-4-piperidone (TMP) | Partial ganglionic blocking mediated |
Marasmius androsaceus
|
Vasodilation |
Tricholoma giganteum
| |
D-mannitol | Competitive inhibition of ACE |
Pleurotus cornucopiae
|
Oligo peptides | Competitive inhibition of ACE |
Pleurotus cornucopiae
|
Potassium | Hyperpolarization of Na + − pump and/or Kir channels |
Lentinula edodes
|
Lentinan | Vasodilation |
Lentinula edodes
|
Pentapeptide | Stereoselective and competitive |
Pholiota adiposa
|
L-pipecolic acid | Inhibition of ACE |
Sarcodona spratus
|
Hexapeptide | Inhibition of ACE |
Grifola frondosa
|
Maleic/succinic acid derivatives, triterpenoids, benzenoids, and benzoquinone derivatives | Reduced the aggregation and phosphorylation of PKC in phorbol-12,13-dibutyrate (PDBu)-activated platelets |
Antrodia camphorata Lu et al. (2014) |
Oligo peptides, protein extract | Inhibition of ACE |
Agaricus bisporus Lau et al. (2012) |
Table 11.2
ACE inhibitory activity of extracts of different mushrooms
Species | ACE inhibitory activity (%) | Reference |
|---|---|---|
Leucopaxillus tricolor
| 95.0 | |
Grifola frondosa
| 77.2 | Geng et al. (2015) |
Boletus bicolor
| 61.3 | Ibadallah et al. (2015) |
Tuber micheli
| 56.5 | Geng et al. (2015) |
Russula aeruginea
| 53.1 | Geng et al. (2015) |
Boletus edulis
| 47.2 | Abdullah et al. (2012) |
Morchella vulgaris
| 43.3 | Robati et al. (2014) |
Ramaria botrytoides
| 37.8 | Geng et al. (2015) |
Oudemansiella radicata
| 30.8 | Geng et al. (2015) |
Gloeostereum incarnatum
| 29.2 | Geng et al. (2015) |
Tricholoma matsutake
| 95.0 | Geng et al. (2016) |
Tricholoma terreum
| 35.3 | Geng et al. (2015) |
Tricholoma saponaceum
| 38.2 | Geng et al. (2016) |
Tricholoma giganteum
| 29.7 | Geng et al. (2016) |
11.3.4 Anti-obesity Effects
Obesity is a widespread problem and it is estimated that more than one third of adults in the United States are obese (Feeney et al. 2014; Poddar et al. 2013). Obesity is often associated with hyperlipidemia and is also commonly related with improper diet and life style. Various mushrooms have shown efficient hypocholesterolemic effects. β-1,3-D-Glucan of mushrooms are known to interact with bile acids and affect micella aggregates that may interfere in the process of cholesterol absorption (Bobek et al. 1996). Pleurotus ostreatus, Lentinus lepideus, Panellus serotinus, and Lentinus edodes are some of the well-known mushrooms with anti-obesity effects (Bobek et al. 1996; Handayani et al. 2011; Yoon et al. 2011).
11.4 Major Constituents of Mushroom with Cardioprotective Potential
The most commonly cultivated mushroom is Agaricus bisporus followed by Lentinus edodes, Pleurotus spp., and Flammulina velutipes. China is one of the leading producers of mushrooms in the world (Aida et al. 2009; Valverde et al. 2015). However, wild mushrooms are attracting increasing interest for their nutritional and pharmacological characteristics (Barros et al. 2008; Kalac 2013).
Mushrooms are rich in carbohydrates and have a high content of proteins and significant levels of vitamins including vitamin B1, B2, B12, C, and D and minerals such as Ca, K, Mg, Na, P, Cu, Fe, Mn, and Se. The moisture content of mushrooms is generally high (81.8–94.8%). The crude proteins content of mushrooms varies from 15.2 g/100 g in L. edodes to 80.93 g/100 g dried weight in A. bisporus. Total protein contents (dried weight) account for 0.47 g and 1.29 g per 100 g in F. velutipes and A. bisporus, respectively.
A plethora of molecules from the mushrooms are known to have bioactive properties and are generally found in the fruiting bodies. Experimental evidences on laboratory and farm-grown mushrooms show high levels of polysaccharides, proteins, fats, minerals, glycosides, alkaloids, volatile oils, terpenoids, tocopherols, phenolics, flavonoids, carotenoids, folates, lectins, enzymes, ascorbic, and organic acids. A large number of bioactive substances, about 150 in Pleurotus and 400 in Ganoderma, have been studied so far. The bioactive components of mushrooms are potent immune modulators and have systemic effects in the body.
However, polysaccharides especially β-glucans in mushrooms are the most researched bioactive substances and are known for their immune-modulatory effects. With reference to their water solubility, dietary fibers are categorized as insoluble form (chitin, cellulose, lignin) and soluble form (β-glucans and chitosans). Polysaccharides also possess cardioprotective effects against obesity-associated cardiac disorders as they are shown to possess hyperlipidemic effects. The antioxidant properties of polysaccharides (Chen et al. 2015; He et al. 2012) may protect the heart from ischemia/reperfusion injury. Polysaccharides of edible mushrooms are composed of D-mannose, D-galactose and D-glucose, L-Arabinose, L-fucose, L-rhamnose, D-ribose, and D-xylose (He et al. 2012).
Apart from polysaccharides, nucleotides also constitute an important group of bioactive compounds in mushrooms. Adenosine is an important bioactive nucleotide with cardioprotective effects. Nucleotides are known for their vasodilation potential and thus can influence every organ in a systemic way. Also, nucleotides possess antiplatelet properties, enhance circulation, act as a potential muscle relaxant, and reduce stress.
In addition, mushrooms are rich in phenolic compounds particularly phenolic acids with antioxidant properties and act as efficient cardioprotectants. Some of the phenolic acids from mushroom with strong antioxidant activity include caffeic acid, p-hydroxybenzoic, gallic acid, protocatechuic acid, p-Coumaric acid, and cinnamic acid which have been proved to be efficient cardioprotective agents both in vitro and in vivo studies (Mattila et al. 2001).
Mushroom proteins are rich in glutamic acid, aspartic acid, and arginine. Uncommon bioactive amino acids such as γ-amino butyric acid (GABA) and ornithine also add up to the biological effects of mushroom proteins. Apart from the protein-associated nitrogen content, mushrooms possess high levels of nonprotein sources of nitrogen (Valverde et al. 2015). Common edible mushrooms contain high levels of proteins in their fruiting bodies (4.5% in L. edodes, 31% in Agaricus blazei) (Valverde et al. 2015
). The total amino acid content and essential amino acid contents were 93.6–230 and 39.7–86.8 g/kg, respectively, in 11 wild species. Methionine was the least abundant, while glutamic acid was the most abundant amino acid. Glutamic acid content was 37.6 g/kg dry weight in Leucopaxillus giganteus and 10.9 g/kg dry weight in Cantharellus tubaeformis. Total free amino acid content in wild species varied from 1.5 to 72 g/kg of dry weight depending on the mushroom species.
The vitamin and mineral contents in mushrooms are said to be higher than those found in most vegetables (Barros et al. 2008; Mattila et al. 2001). Mushrooms are composed of rich vitamin content such as vitamin D (ergosterol), vitamin B complex (riboflavin, niacin, biotic, folic acid), vitamin B12 (cobalamin) and B5 (pantothenic acid), and vitamin C (L-ascorbic acid), E, H (Biotin), K, and PP (Niacin) and have potent cardioprotective function (Hansen et al. 2015, 2017). The riboflavin contents in edible mushrooms are very high like those present in vegetables, and in some mushrooms like Agaricus bisporus, the contents are as high as found in eggs and cheese. Minerals including magnesium, potassium, manganese, sodium, iron, selenium, and zinc have been reported from mushrooms.
Edible mushrooms offer low quantities of dietary fat. Unsaturated fatty acids constitute the major content over the saturated fatty acids particularly palmitic acid, oleic acid, and linoleic acid. Linolenic acid is a precursor for 1-octen-3-ol, commonly identified as mushroom alcohol, a chief aromatic compound present in wide varieties of fungi and responsible for mushroom flavor (Pinho et al. 2008). Unsaturated fatty acids are very critical for cellular metabolism and normal functioning of the human body. The total fatty acid content in the edible fruiting bodies of Cantharellus cibarius has been estimated to be 3.6 g/100 g of dry weight. Contents of total lipids are low in wild varieties of mushrooms (between 20 and 30 g/kg dry weight). Some of the common fatty acids in wild mushrooms are linoleic acid, oleic acid, and palmitic acid although in reasonably low quantities (Kalac 2013).
11.5 Mushrooms for Reducing the Risk of CVD
11.5.1 Lentinus edodes (Shiitake)
High cholesterol level is one of the most critical risk factors for cardiovascular diseases. There is a strong correlation between hyperlipidemia and CVD associated mortality. Lentinus edodes (Fig. 11.1a), a macrofungus popularly known as shiitake, is used as a traditional medicine in Korea, Japan, and China for its blood cholesterol-lowering effects. According to a study rats fed with a dietary supplement containing 5% L. edodes fruiting bodies for 10 weeks showed a significant reduction in their plasma cholesterol levels (Kaneda and Tokuda 1966). In another study, L. edodes was found to be effective as an antioxidant at 100 and 400 mg/kg in rats. However, dosage higher than 400 mg/kg caused undesirable changes like reductions in hemoglobin and leukocyte content in the blood (Grotto et al. 2016). Administration of L. edodes in rat models caused reduction in the lipidemia-related factors such as cholesterol, HDL cholesterol, and non-HDL cholesterol and serum triglyceride. However, its effect on serum leptin concentrations was noted in females but not in males indicating its potential to modulate estrogen-associated serum leptin level (Shimizu et al. 1997; Tanaka et al. 2001; Yu et al. 2016). Water-soluble components of L. edodes containing polysaccharides were capable of inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the endogenous cholesterol biosynthesis (Gil-Ramirez et al. 2016). In addition to the therapeutic effects in animal models, L. edodes also showed effective serum cholesterol-lowering effects in humans. Consumption of fresh L. edodes or its dried form or UV-irradiated dried samples reduced serum cholesterol within 7 days in younger as well as in adult women (Bisen et al. 2010).
Fig. 11.1
Fruiting bodies of mushrooms that potentially reduce the risk of CVD. (a) Lintinula edodes, (b) Clitocybe nuda, (c) Boletus aestivalis, (d) Ganoderma lucidum, (e) Pleurotus eryngii, (f) Hypsizygus marmoreus (*Attribution: Dan Molter (shroomydan) (https://commons.wikimedia.org/wiki/File:Clitocybe_nuda_60302.jpg), “Clitocybe nuda 60302”, https://creativecommons.org/licenses/by-sa/3.0/legalcode
Eritadenine (2(R), 3(R)-dihydroxy-4-(9-adenyl)-butyric acid) is a hypocholesterolemic factor isolated from L. edodes and is considered to be one of the major active components responsible for the cholesterol-lowering properties of this mushroom species (Chibata et al. 1969; Rokujo et al. 1970). The hyperlipidemic effects of eritadenine have been widely explored. It lowers the levels of both high-density and low-density lipoproteins. The cholesterol-reducing effect is not by inhibiting the cholesterol biosynthesis but possibly due to accelerating the cholesterol excretion and decomposition. Dietary addition of eritadenine (0.005%) in rats resulted in a 25% reduction in total cholesterol within a week. It was found to be more effective in rats on high fat diet than in those on a low-fat diet. A study on humans also indicated a similar effect (Bisen et al. 2010).
11.5.2 Clitocybe nuda
These edible mushrooms (Fig. 11.1b) are commonly known as wood blewit or blue stalk and are found in Europe, North America, Asia, and Australia (Barros et al. 2008). Due to its distinct fragrance and delicacy, it is preferably cultivated in France, Holland, Britain, and Taiwan. Bioactive extracts of C. nuda are known to exhibit antioxidant properties (Murcia et al. 2002). The ethanol extracts of C. nuda contain 48.01 μg/mg pyrocatechol, and 8.21 μg/mg quercetin considered as efficient free radical scavengers, terminating the radical chain reactions occurring during the oxidation of triglyceride and account for the antioxidant properties (Mercan et al. 2006; Velioglu et al. 1998).
Drimane sesquiterpenoid such as 3-keto-drimenol, 3β-hydroxydrimenol, and 3β,11,12-trihydroxydrimene from Clitocybe has shown to inhibit two isozymes of 11 β-hydroxysteroid dehydrogenases (11 -βHSD1) that are oxidoreductases catalyzing the interconversion of active cortisol and inactive cortisone (Xu et al. 2009). Inhibitors of 11 -βHSD1 are known to have a potential treatment for metabolic syndrome associated with modulation in androgen and estrogen hormones that play a major role in regulating cell survival and protection. Treatment with C. nuda extracts has shown promising anti-obesity effects by significantly increasing GLUT4 levels and phospho-AMP-activated protein kinase (AMPK) in the skeletal muscle, adipose, and liver tissues as observed from STZ-induced diabetic mice models (Shih et al. 2014).
11.5.3 Boletus aestivalis
Boletus aestivalis (Fig. 11.1c) is a very popular mushroom species for its elegant aroma particularly in the Europe and used as an ingredient in traditional medicine. Mushrooms of Boletus sp. are known for their effects in regulating the blood flow and relieving muscle tension and possessing antioxidant and antitumor potential. Hot water extracts of these mushrooms have been shown to possess potential antihypertensive effects and reduced high heart rate as seen in hypertensive rats. Also, in a study by Midoh et al. (2013), hot water extracts of B. aestivalis decreased the levels of blood urea nitrogen, creatinine, and triglyceride and elevated the high-density lipoprotein-cholesterol levels in blood, suggesting that B. aestivalis is an excellent natural nutritional source to ameliorate hypertension-associated cardiac effects (Midoh et al. 2013). Acetone and methanol extracts of B. aestivalis, respectively, contain about 7 μg and 5 μg of pyrocatechol (equivalent/mg of phenolic compounds), and their corresponding flavonoid contents have been shown to be 3 μg and 2 μg of rutin (equivalent/mg of extract). The presence of these phenolics and flavonoids translates to strong antioxidant potential of the extracts and therefore could be the possible reason behind the cardioprotective function, although a direct correlation has not been established so far. Further, the methanol extracts B. aestivalis seems to be less cytotoxic than the acetone extract, a suitable trait for cardioprotective formulations (Kosanic et al. 2012).
11.5.4 Ganoderma lucidum
Ganoderma lucidum (Fig. 11.1d) is a medicinal fungus in the Polyporaceae family and is included extensively as an important constituent in various traditional Chinese medicine formulations. It is mostly cultivated as a medicinal mushroom rather as a dietary mushroom (Jong and Birmingham 1992). G. lucidum has been known to contain more than 300 bioactive ingredients including triterpenes, polysaccharides (e.g., β-glucan), ganoderic acids, proteins, peptides, steroids, and sterols to exert different pharmacological properties. Various compounds of the mushroom show promising hypolipidemic, hepatoprotective, antioxidative, antiatherosclerotic, and anti-inflammatory effects (Hajjaj et al. 2005; Pan et al. 2013; Wang et al. 2012). Hydroalcoholic extracts taken from basidiomata of G. lucidum are shown to reduce the serum total cholesterol levels in high cholesterol fed obese mice models. Various biologically active oxygenated lanostane-type triterpenoids identified from G. lucidum including ganoderal A, ganoderol B, ganoderic acid S, and ganoderic acid K display inhibitory effects on angiotensin-converting enzyme (Morigiwa et al. 1986). G. lucidum extracts also significantly reduce hepatic triglycerides and cholesterol and could be a potential hypocholesterolemic agent (Meneses et al. 2016). 26-oxygenosterols from G. lucidum inhibits lanosterol 14α-demethylase, which converts 24,25-dihydrolanosterol to cholesterol and thereby lowers blood cholesterol levels (Hajjaj et al. 2005). The hepatic lipid reduction properties of G. lucidum extracts are also driven by its ability to reduce key lipogenic genes Srebp1c, Acaca, and Fasn, thereby suppressing hepatic fatty acid synthesis and, hence, hepatic triglyceride accumulation (Meneses et al. 2016).
11.5.5 Pleurotus eryngii
Pleurotus eryngii (Fig. 11.1e) is an edible and therapeutic mushroom in the Pleurotaceae family of the phylum Basidiomycota. The species has shown various biological activities including antioxidant properties and hepatoprotection. Acidic- and alkalic-extractable mycelia zinc polysaccharides extracted from P. eryngii have demonstrated prevention of hyperlipidemic effects (Xu et al. 2017). The polysaccharides in the mushroom are known to increase serum HDL cholesterol levels and decrease LDL cholesterol, VLDL cholesterol, total cholesterol, and triglyceride levels and thereby provide positive effects in hyperglycemia and hyperlipidemia conditions (Chen et al. 2016; Xu et al. 2017). P. eryngii with its strong effects on hyperlipidemic conditions has demonstrated a reduction in atherosclerosis formation in apolipoprotein E-deficient mice correlating with the reduced serum total cholesterol (Mori et al. 2008).
11.5.6 Grifola frondosa
Grifola frondosa is a well-known and widely consumed medicinal fungus found in Japan, European countries, and the northeastern states of America. Polysaccharides from the fruiting bodies of G. frondosa are known to possess antioxidative activities (Chen et al. 2012; He et al. 2017; Mao et al. 2014). G. frondosa also contain active ingredients such as D-(+)-trehalose and crude polysaccharides to counter diabetes and high blood sugar levels due to its inhibitory effects on α-glucosidase (Matsuura et al. 2002). Evidences point out that the antidiabetic effects of an α-glucan from G. frondosa are chiefly due to their effects on insulin receptors, which cause enhanced insulin sensitivity (Hong et al. 2007). G. frondosa SX-fraction with an average molecular weight of 20,000 is a glycoprotein containing a protein to saccharide ratio in the range of 75:25 to 90:10. The SX-fraction has shown to exhibit hypoglycemic activity in diabetic mice and in type 2 patients under clinical conditions. Also, SX-fraction is shown specifically targeting the insulin receptor and thereby triggering the subsequent signaling events and facilitate glucose uptake (Konno et al. 2013).
11.5.7 Hypsizygus marmoreus
Hypsizygus marmoreus (Fig. 11.1f) is an edible mushroom consumed in Korea, Japan, China, North Europe, and East Asia. Dietary supplement of H. marmoreus powder has been found to lower total serum cholesterol and deliver a strong antiatherosclerotic effect in mice (Mori et al. 2008). A purified novel 567.3 Da oligo peptide ACE inhibitor LSMGSASLSP from H. marmoreus has demonstrated a clear antihypertensive action in spontaneously hypertensive rat models (Kang et al. 2013).
11.6 Cardioprotective Mushrooms and Their Metabolites
11.6.1 Pleurotus ostreatus
The oyster mushroom P. ostreatus (Fig. 11.2a) is one the most popular and effective medicinal mushrooms used for protecting the heart. P. ostreatus helps protect from atherosclerosis and reduces cholesterol and diminishes the risk of heart diseases. An extract with 63% polysaccharide content from P. ostreatus was found to regulate dyslipidemia in hyperlipidemia rats and has proven antidiabetic effects in type 2 diabetes rat models (Zhang et al. 2016, 2017). P. ostreatus has abundance of phenolic compounds such as protocatechuic acid (81 μg/g dry weight), followed by gallic acid (36 μg/g dry weight), chlorogenic acid (27 μg/g dry weight), formononetin (14 μg/g dry weight), naringenin (10 μg/g dry weight), hesperetin (10 μg/g dry weight), and biochanin A (10 μg/g). Alam et al. have reported phenolic contents of P. ostreatus showing antioxidant activity (Alam et al. 2010). Also, these act as antihyperlipidemic agents.
Fig. 11.2
Fruiting bodies of mushrooms effective against CVD: (a) Pleurotus ostreatus, (b) Auricularia auricular. *Attribution Thomas Pruß (https://commons.wikimedia.org/wiki/File:Judasohr_(11).jpg), “Judasohr (11)”, https://creativecommons.org/licenses/by-sa/3.0/legalcode
11.6.2 Agaricus brasiliensis
Polysaccharides produced by the edible and pharmacologically important mushroom A. brasiliensis (previously name: A. blazei) have attracted considerable interest primarily due to its antimutagenic effects (Borchers et al. 2004). Also, recent reports show that A. brasiliensis has been known to possess cardioprotective functions and anti-inflammatory activity. The extracts of A. brasiliensis are found to contain significant amounts of minerals such as calcium, zinc, iron, magnesium, and phosphorus and are effective against diabetes mellitus, atherosclerosis, and hyperlipidemia which are the major risk factors for CVD. Although consumption of A. brasiliensis in rats showed no morphological changes in the heart, it could significantly enhance the antioxidant enzyme super oxide dismutase and reduce the lipid peroxidation-associated oxidative damage marker malondialdehyde (Zhang et al. 2010).
Polysaccharides of A. brasiliensis have been identified to be the principle factors that carry out cardioprotective function against ischemia reperfusion. The effective cardioprotective fraction of the A. brasiliensis was majorly polysaccharides, typically heteropolysaccharides, and mainly of glucose, arabinose, and mannose in the molar percentages of 78.38%, 10.46%, and 8.51%, respectively (Zhang et al. 2010).
11.6.3 Auricularia auricula
The fruiting bodies of A. auricula (Fig. 11.2b) have long been used both as a food and as traditional medicine in China. The fruiting body of this mushroom is composed of high levels of polysaccharides, containing approximately 630 g kg−1 carbohydrates (on dried weight basis). The total polysaccharide content is composed of glucose, 8% mannose, 10% xylose, and 10% fucose (Wu et al. 2010a). Also, fruiting bodies contain higher levels of proteins with Lys and Leu amino acids and minerals such as Ca, P, and Fe. Among the most mushrooms, polysaccharides of A. auricula are the most studied and found to be highly effective bioactive ingredients possessing antioxidant, anticoagulant hyperlipidemic, and antidiabetic activities (Chen et al. 2008; Fan et al. 2007; Hu et al. 2017; Luo et al. 2009).
The sulfation of acid A. auricula polysaccharides and the sulfation of neutral A. auricula polysaccharides derivatives possess considerable antioxidant activity.
Polysaccharides extracted from A. auricula evidently regulate serum triglycerides and LDL-C levels and enhance the antioxidant capacity in experimental animals (Chen et al. 2008). Administration of A. auricula polysaccharides acts as an effective natural antioxidant that safeguards cardiac function by maintaining the redox levels in the heart. Also, A. auricula polysaccharides enhance the ejection fraction (EF) and shot axis fractional shortening (FS) parameters of the left ventricles in aged mice models and therefore are efficient cardioprotective agents that improve heart function and retard the aging process (Wu et al. 2010a).
11.6.4 Inonotus xeranticus
Inonotus xeranticus, a mushroom that lives on deciduous trees such as Quercus species, is distributed in Korea, Japan, and China. Davallialactone is an active hispidin analog which is also found in several other mushroom species, e.g., Davallia mariesii and Phellinus igniarius. Davallialactone is known to possess antiplatelet aggregation activity, antioxidant activity, and free radical scavenging properties (Kim et al. 2008; Lee et al. 2008). Davallialactone has been reported to trigger anti-inflammatory effects by suppressing NfκB via PI3K, Akt, and IKK and independent of MAPKs. Administration of davallialactone strongly affects the LPS-induced phosphorylation and kinase activity of Src, thereby revealing that Src is involved in cardiac hypertrophic conditions (Takeishi et al. 2001). Davallialactone effectively attenuates Adriamycin-associated cardiac damages by maintaining the levels of antioxidant enzymes, protecting mitochondria from ROS effects, suppressing apoptosis effects, and thus restoring cardiac function (Arunachalam et al. 2012).
11.7 Active Ingredients and Their Cardioprotective Mechanism
11.7.1 Formononetin
As a major isoflavone compound in P. ostreatus, formononetin (Fig. 11.3) has exhibited a wide range of pharmacological properties such as anticancer, anti-inflammatory, antioxidant, anti-apoptosis, neuroprotection against ischemia/reperfusion injury, and wound healing (Auyeung et al. 2012; Huh et al. 2011; Jia et al. 2014; Jin et al. 2014; Liang et al. 2014; Ma et al. 2013; Sun et al. 2012). Formononetin protects cardiomyocytes from OGD/reoxygenation injury via inhibiting ROS formation and by promoting GSK-3 β phosphorylation and maintaining mitochondrial membrane permeability (Cheng et al. 2016). As a phytoestrogen, formononetin has been shown to reduce arterial stiffness and regulate blood pressure in overweight men and postmenopausal women (Nestel et al. 2007; Xing et al. 2010).
Fig. 11.3
Chemical structures of compounds with cardioprotective mechanism. (a) Formononetin, (b) gallic acid, (c) chlorogenic acid, (d) naringenin, (e) biochanin A, (f) hispidin, (g) fomiroid A, (h) lovastatin
11.7.2 Gallic Acid
Gallic acid (Fig. 11.3b) is a metabolite of propyl gallate and is known to activate diverse pharmacological and biochemical effects including strong anticancer, antioxidant, and anti-inflammatory (Inoue et al. 1995; Kim et al. 2002; Kroes et al. 1992; Shahrzad et al. 2001).
Gallic acid has been widely studied for its cardioprotective effects. It effectively lowers blood pressure and attenuates hypertension regardless of the administration route (IP or oral). Gallic acid administration for 3–7 weeks reduced hypertension-associated left-ventricle posterior wall, and septum thickness in chronic L-NAME induced hypertensive mice. Short-term or long-term treatment with gallic acid also attenuates cardiac fibrosis and reduces the levels of histone deacetylase (HDAC) 1 and HDAC 2 in H9c2 cells in rat primary cardiac fibroblasts and as well as in animal models (Jin et al. 2017).
Gallic acid also reduces the DNA-binding ability of phosphorylated Smad3 to Smad binding sites of collagen type I promoter and attenuates cardiac fibroblasts in rats. Further, it also decreases the isoproterenol-induced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) protein in mice (Ryu et al. 2016). It was found that gallic acid pretreatment decreased isoproterenol-induced changes in the levels of cardiac marker enzymes such as creatine kinase, aspartate transaminase, alanine transaminase, and lactate dehydrogenase indicating a protective effect against cardiac injury. Also, it elevated the levels of enzymatic and nonenzymatic antioxidants (Priscilla and Prince 2009).
11.7.3 Chlorogenic Acid
Chlorogenic acid (Fig. 11.3c) is an ester of caffeic and quinic acids and is considered as one of the most abundant polyphenol compounds in human diet with proven biological effects determined by in vitro and in vivo investigations (Suzuki et al. 2002). Chlorogenic acid exhibits various pharmacological properties such as anticancer, antioxidant, and antihypertensive in humans (Kozuma et al. 2005; Laranjinha et al. 1994; Morishita et al. 1997; Rodriguez de Sotillo and Hadley 2002; Suzuki et al. 2002). Administration of 5-caffeoylquinic acid, a representative of chlorogenic acid, in spontaneously hypertensive rats reduced oxidative stress and improved nitric oxide bioavailability by inhibition of excessive production of reactive oxygen species (ROS) in the vasculature and attenuated endothelial dysfunction, vascular hypertrophy, and hypertension (Suzuki et al. 2006). Administration of chlorogenic acid at a concentration of 40 mg/kg body weight for 19 days effectively ameliorated ISO-induced alterations in cardiac functional parameters and noticeably restored the activities of heart mitochondrial enzymes in ISO-induced rats and reduced the stress in the heart (Akila et al. 2017).
11.7.4 Naringenin
Naringenin (Fig. 11.3d) is one of the naturally occurring bioflavonoids with antioxidant, anti-inflammatory, and anticancer properties (Banjerdpongchai et al. 2016). Naringenin regulates the antioxidant enzyme system and controls successive lipid peroxidation to ameliorate doxorubicin induced toxicity and hypoxic stress (Kathiresan et al. 2016). Also, naringenin attenuates the mRNA expression levels of critical inflammatory markers induced by doxorubicin, alleviates cardiac damage, and improves cardiac functions.
11.7.5 Biochanin A
Biochanin A (Fig. 11.3e) possesses a wide range of bioactivities and multiple mechanisms to protect against diabetes, cancer, inflammation. It is a powerful radical scavenger in the presence of a transition metal ion. Biochanin A reverts arsenic challenge caused by oxidative stress, triglyceride, and lipoprotein levels in cardiac tissues. Thereby, it effectively establishes protective effect against arsenic induced cardiotoxicity (Jalaludeen et al. 2015). Biochanin A triggers the relaxation in aortic rings in normal and hypertensive rats by acting on ATP-sensitive potassium channels (Wang et al. 2006).
11.7.6 Hispidin
Hispidin (Fig. 11.3f), a phenolic compound isolated from Phellinus linteus, has been found to possess effective antioxidant, anticancer, antidiabetic, and anti-dementia properties. Hispidin is a PKC inhibitor, thereby a potential cardioprotective agent. Hispidin has been shown to protect H9c2 cardiomyoblast cells against H2O2-induced oxidative stress-associated apoptosis via Akt/GSK-3β and ERK1/2signaling pathways. Hispidin effectively inhibits the intracellular ROS generation by elevating the antioxidant enzymes such as heme oxygenase, catalase, and superoxide dismutase (Kim et al. 2014; Yang et al. 2014).
11.7.7 Fomiroid A
Fomiroid A (Fig. 11.3g) has been identified as an active principle of F. nigra contributing its hypercholesterolemia property. Fomiroid A, a structural analog of lanosterol (a precursor of cholesterol biosynthesis), directly binds to NPC1L1 which is a key protein in cholesterol absorption. Fomiroid A effectively inhibits NPC1L1-mediated cholesterol uptake via direct interaction with NPC1L1 (Chiba et al. 2014).
11.7.8 Lovastatin
Lovastatin (Fig. 11.3h) is a naturally occurring statin drug administered to those with hypercholesterolemia for its cholesterol-lowering effect and thus reduced cardiovascular disease. Lovastatin is found in mushrooms such as Pleurotus ostreatus as a phyto-complex, and, therefore, naturally occurring lovastatin does not exhibit the side effects observed in synthetic statins. Mushroom-derived statins contain other ingredients as a complex to mitigate the side effects (Alarcon and Aguila 2006). They act by competitive interaction and inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, an enzyme of the cholesterol production. Lovastatin effectively prevents angiotensin II-induced cardiac hypertrophy by enhancing p21ras/MAP kinase pathway (Oi et al. 1999). Lipid-lowering effect of lovastatin helped in improving the LV systolic function and decreased myocardial ischemia in patients with coronary artery disease (Kerimkulova et al. 2011).
11.8 Conclusions
Drastic changes in the environment and lifestyle-associated effects on healthy life of humans have resulted in the search for various functional foods to acquire desired protective effects. A diverse variety of mushrooms and their constituents have been explored for their distinct flavor and taste for years and have been supplemented in the diet for its therapeutic potential. Mushrooms offer a complete source of nourishment and dietary bioactive elements apart from being rich in protein, dietary fiber, vitamins, and mineral substances. Mushrooms are a Pandora box with a massive number of bioactive components. However, the treasure trove mushrooms offer need to be explored extensively. Identification of bioactive metabolites in mushrooms is a key component to develop its therapeutic values. Mushrooms have shown extraordinary potential to counter or to treat cardiac diseases. However, progresses in development of commercially viable therapeutic drugs are still wanting. Therefore, concerted efforts are needed for further exploration and documentation of potential bioactive ingredients from medicinal mushrooms, its merits and demerits, and finally development of commercially viable drugs/products.
References
Abdullah N, Ismail SM, Aminudin N, Shuib AS, Lau BF (2012) Evaluation of selected culinary-medicinal mushrooms for antioxidant and ACE inhibitory activities. Evid Based Complement Altern Med: eCAM 2012:464238. doi:10.1155/2012/464238
Aida FMNA, Shuhaimi M, Yazid M, Maaruf AG (2009) Mushroom as a potential source of prebiotics: a review. Trends Food Sci Technol 20:567–575. doi:10.1016/j.tifs.2009.07.007
Akila P, Asaikumar L, Vennila L (2017) Chlorogenic acid ameliorates isoproterenol-induced myocardial injury in rats by stabilizing mitochondrial and lysosomal enzymes. Biomed Pharmacother 85:582–591. doi:10.1016/j.biopha.2016.11.067
PubMed
Alam N et al (2010) Antioxidant activities and tyrosinase inhibitory effects of different extracts from Pleurotus ostreatus fruiting bodies. Mycobiology 38:295–301. doi:10.4489/MYCO.2010.38.4.295
PubMedPubMedCentral
Alarcon J, Aguila S (2006) Lovastatin production by Pleurotus ostreatus: effects of the C:N ratio. Z Naturforsch 61:95–98
Arunachalam S et al (2012) Davallialactone protects against adriamycin-induced cardiotoxicity in vitro and in vivo. J Nat Med Tokyo 66:149–157. doi:10.1007/s11418-011-0567-1
Auyeung KK, Law PC, Ko JK (2012) Novel anti-angiogenic effects of formononetin in human colon cancer cells and tumor xenograft. Oncol Rep 28:2188–2194. doi:10.3892/or.2012.2056
PubMed
Banjerdpongchai R, Wudtiwai B, Khaw-on P, Rachakhom W, Duangnil N, Kongtawelert P (2016) Hesperidin from citrus seed induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways. Tumor Biol 37:227–237. doi:10.1007/s13277-015-3774-7
Barros L, Calhelha RC, Vaz JA, Ferreira ICFR, Baptista P, Estevinho LM (2007) Antimicrobial activity and bioactive compounds of Portuguese wild edible mushrooms methanolic extracts. Eur Food Res Technol 225:151–156. doi:10.1007/s00217-006-0394-x
Barros L, Cruz T, Baptista P, Estevinho LM, Ferreira ICFR (2008) Wild and commercial mushrooms as source of nutrients and nutraceuticals. Food Chem Toxicol 46:2742–2747. doi:10.1016/j.fct.2008.04.030
PubMed
Barros L, Venturini BA, Baptista P, Estevinho LM, Ferreira IC (2008) Chemical composition and biological properties of portuguese wild mushrooms: a comprehensive study. J Agric Food Chem 56:3856–3862. doi:10.1021/jf8003114
PubMed
Bisen PS, Baghel RK, Sanodiya BS, Thakur GS, Prasad GB (2010) Lentinus edodes: a macrofungus with pharmacological activities. Curr Med Chem 17:2419–2430PubMed
Bobek P, Ozdin L, Kuniak L (1996) Effect of oyster mushroom (Pleurotus Ostreatus) and its ethanolic extract in diet on absorption and turnover of cholesterol in hypercholesterolemic rat die. Nahrung 40:222–224PubMed
Boh B, Berovic M, Zhang J, Zhi-Bin L (2007) Ganoderma lucidum and its pharmaceutically active compounds. Biotechnol Annu Rev 13:265–301. doi:10.1016/S1387-2656(07)13010-6
PubMed
Borchers AT, Keen CL, Gershwin ME (2004) Mushrooms, tumors, and immunity: an update. Exp Biol Med 229:393–406
Chen GT, Ma XM, Liu ST, Liao YL, Zhao GQ (2012) Isolation, purification and antioxidant activities of polysaccharides from Grifola frondosa. Carbohydr Polym 89:61–66. doi:10.1016/j.carbpol.2012.02.045
PubMed
Chen J, Shi Y, He L, Hao H, Wang B, Zheng Y, Hu C (2016) Protective roles of polysaccharides from Ganoderma lucidum on bleomycin-induced pulmonary fibrosis in rats. Int J Biol Macromol 92:278–281. doi:10.1016/j.ijbiomac.2016.07.005
PubMed
Chen PY, Yong YY, Gu YF, Wang ZL, Zhang SZ, Lu L (2015) Comparison of antioxidant and antiproliferation activities of polysaccharides from eight species of medicinal mushrooms. Int J Med Mushrooms 17:287–295PubMed
Chen L, Zhang Y, Sha O, Xu W, Wang S (2016) Hypolipidaemic and hypoglycaemic activities of polysaccharide from Pleurotus eryngii in Kunming mice. Int J Biol Macromol 93:1206–1209. doi:10.1016/j.ijbiomac.2016.09.094
PubMed
Chen G et al (2008) Effect of polysaccharide from Auricularia auricula on blood lipid metabolism and lipoprotein lipase activity of ICR mice fed a cholesterol-enriched diet. J Food Sci 73:H103–H108PubMed
Cheng YY, Xia ZY, Han YF, Rong JH (2016) Plant natural product formononetin protects rat cardiomyocyte H9c2 cells against oxygen glucose deprivation and reoxygenation via inhibiting ROS formation and promoting GSK-3 beta phosphorylation. Oxid Med Cell Longev doi:Artn 206087410.1155/2016/2060874
Chiba T et al (2014) Fomiroid A, a novel compound from the mushroom Fomitopsis nigra, inhibits NPC1L1-mediated cholesterol uptake via a mode of action distinct from that of ezetimibe. PLoS One 9:e116162. doi:10.1371/journal.pone.0116162
PubMedPubMedCentral
Chibata I, Okumura K, Takeyama S, Kotera K (1969) Lentinacin: a new hypocholesterolemic substance in Lentinus edodes. Experientia 25:1237–1238PubMed
Chien RC et al (2016) Anti-inflammation properties of fruiting bodies and submerged cultured mycelia of culinary-medicinal higher basidiomycetes mushrooms. Int J Med Mushrooms 18:999–1009. doi:10.1615/IntJMedMushrooms.v18.i11.50
PubMed
da Costa MC, Regina M, Ciliao Filho M, Linde GA, do Valle JS, Paccola-Meirelles LD, Colauto NB (2015) Photoprotective and antimutagenic activity of Agaricus subrufescens basidiocarp extracts. Curr Microbiol 71:476–482. doi:10.1007/s00284-015-0859-x
PubMed
De Mello WC, Danser AHJ (2000) Angiotensin II and the heart on the intracrine renin-angiotensin system. Hypertension 35:1183–1188. doi:10.1161/01.hyp.35.6.1183
PubMed
Fan LS, Zhang SH, Yu L, Ma L (2007) Evaluation of antioxidant property and quality of breads containing Auricularia auricula polysaccharide flour. Food Chem 101:1158–1163. doi:10.1016/j.foodchem.2006.03.017
Feeney MJ et al (2014) Mushrooms and health summit proceedings. J Nutr 144:1128S–1136S. doi:10.3945/jn.114.190728
PubMedPubMedCentral
Ferreira IC, Barros L, Abreu RM (2009) Antioxidants in wild mushrooms. Curr Med Chem 16:1543–1560PubMed
Ganeshpurkar A, Bhadoriya SS, Pardhi P, Jain AP, Rai G (2011) In vitro prevention of cataract by oyster mushroom Pleurotus florida extract on isolated goat eye lens. Indian J Pharm 43:667–670. doi:10.4103/0253-7613.89823
Geng X, Tian G, Zhang W, Zhao Y, Zhao L, Wang H, Ng TB (2016) A Tricholoma matsutake peptide with angiotensin converting enzyme inhibitory and antioxidative activities and antihypertensive effects in spontaneously hypertensive rats. Sci Rep 6:24130. doi:10.1038/srep24130
PubMedPubMedCentral
Geng X et al (2015) Isolation of an angiotensin I-converting enzyme inhibitory protein with antihypertensive effect in spontaneously hypertensive rats from the edible wild mushroom Leucopaxillus tricolor. Molecules 20:10141–10153. doi:10.3390/molecules200610141
PubMed
Gil-Ramirez A et al (2016) Water-soluble compounds from Lentinula edodes influencing the HMG-CoA reductase activity and the expression of genes involved in the cholesterol metabolism. J Agric Food Chem 64:1910–1920. doi:10.1021/acs.jafc.5b05571
PubMed
Grotto D, Bueno DC, Ramos GK, da Costa SR, Spim SR, Gerenutti M (2016) Assessment of the safety of the shiitake culinary-medicinal mushroom, Lentinus edodes (Agaricomycetes), in rats: biochemical, hematological, and antioxidative parameters. Int J Med Mushrooms 18:861–870PubMed
Hajjaj H, Mace C, Roberts M, Niederberger P, Fay LB (2005) Effect of 26-oxygenosterols from Ganoderma lucidum and their activity as cholesterol synthesis inhibitors. Appl Environ Microbiol 71:3653–3658. doi:10.1128/Aem.71.7.3653-3658.2005
PubMedPubMedCentral
Handayani D, Chen J, Meyer BJ, Huang XF (2011) Dietary shiitake mushroom (Lentinus edodes) prevents fat deposition and lowers triglyceride in rats fed a high-fat diet. J Obes 2011:258051. doi:10.1155/2011/258051
PubMedPubMedCentral
Hansen CS, Fleischer J, Vistisen D, Ridderstrale M, Jensen JS, Jorgensen ME (2017) High and low vitamin D level is associated with cardiovascular autonomic neuropathy in people with type 1 and type 2 diabetes. Diabet Med 34:364–371. doi:10.1111/dme.13269
PubMed
Hansen CS, Ridderstrale M, Fleischer J, Vistisen D, Jorgensen ME (2015) Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes. Diabetologia 58:S508–S508
He JZ, Ru QM, Dong DD, Sun PL (2012) Chemical characteristics and antioxidant properties of crude water soluble polysaccharides from four common edible mushrooms. Molecules 17:4373–4387. doi:10.3390/molecules17044373
PubMed
He X et al (2017) Polysaccharides in Grifola frondosa mushroom and their health promoting properties: a review. Int J Biol Macromol 101:910–921. doi:http://doi.org/10.1016/j.ijbiomac.2017.03.177
PubMed
Hobbs FD (2004) Cardiovascular disease: different strategies for primary and secondary prevention? Heart 90:1217–1223. doi:10.1136/hrt.2003.027680
PubMedPubMedCentral
Hong L, Xun M, Wutong W (2007) Anti-diabetic effect of an alpha-glucan from fruit body of maitake (Grifola frondosa) on KK-Ay mice. J Pharm Pharmacol 59:575–582. doi:10.1211/jpp.59.4.0013
PubMed
Hu X et al (2017) Hpyerglycemic and anti-diabetic nephritis activities of polysaccharides separated from Auricularia auricular in diet-streptozotocin-induced diabetic rats. Exp Ther Med 13:352–358. doi:10.3892/etm.2016.3943
PubMed
Huh JE, Nam DW, Baek YH, Kang JW, Park DS, Choi DY, Lee JD (2011) Formononetin accelerates wound repair by the regulation of early growth response factor-1 transcription factor through the phosphorylation of the ERK and p38 MAPK pathways. Int Immunopharmacol 11:46–54. doi:10.1016/j.intimp.2010.10.003
PubMed
Ibadallah BX, Abdullah N, Shuib AS (2015) Identification of angiotensin-converting enzyme inhibitory proteins from mycelium of Pleurotus pulmonarius (oyster mushroom). Planta Med 81:123–129. doi:10.1055/s-0034-1383409
PubMed
Inoue N, Inafuku M, Shirouchi B, Nagao K, Yanagita T (2013) Effect of Mukitake mushroom (Panellus serotinus) on the pathogenesis of lipid abnormalities in obese, diabetic ob/ob mice. Lipids Health Dis 12:18. doi:10.1186/1476-511X-12-18
PubMedPubMedCentral
Inoue M et al (1995) Selective induction of cell death in cancer cells by gallic acid. Biol Pharm Bull 18:1526–1530PubMed
Jalaludeen AM, Lee WY, Kim JH, Jeong HY, Ki KS, Kwon EG, Song H (2015) Therapeutic efficacy of biochanin A against arsenic-induced renal and cardiac damage in rats. Environ Toxicol Pharmacol Pharmacol 39:1221–1231. doi:10.1016/j.etap.2015.04.020
Ji ZS, Sanan DA, Mahley RW (1995) Intravenous heparinase inhibits remnant lipoprotein clearance from the plasma and uptake by the liver: in vivo role of heparan sulfate proteoglycans. J Lipid Res 36:583–592PubMed
Jia WC, Liu G, Zhang CD, Zhang SP (2014) Formononetin attenuates hydrogen peroxide (H2O2)-induced apoptosis and NF-kappaB activation in RGC-5 cells. Eur Rev Med Pharmacol Sci 18:2191–2197PubMed
Jin YM, Xu TM, Zhao YH, Wang YC, Cui MH (2014) In vitro and in vivo anti-cancer activity of formononetin on human cervical cancer cell line HeLa. Tumour Biol 35:2279–2284. doi:10.1007/s13277-013-1302-1
PubMed
Jin L et al (2017) Gallic acid attenuates hypertension, cardiac remodeling, and fibrosis in mice with NG-nitro-L-arginine methyl ester-induced hypertension via regulation of histone deacetylase 1 or histone deacetylase 2. J Hypertens. doi:10.1097/HJH.0000000000001327
Jong SC, Birmingham JM (1992) Medicinal benefits of the mushroom Ganoderma. Adv Appl Microbiol 37:101–134. doi:10.1016/S0065-2164(08)70253-3
PubMed
Kabir Y, Yamaguchi M, Kimura S (1987) Effect of shiitake (Lentinus edodes) and maitake (Grifola frondosa) mushrooms on blood pressure and plasma lipids of spontaneously hypertensive rats. J Nutr Sci Vitaminol (Tokyo) 33:341–346
Kajaba I, Simoncic R, Frecerova K, Belay G (2008) Clinical studies on the hypolipidemic and antioxidant effects of selected natural substances. Bratisl Lek Listy 109:267–272PubMed
Kalac P (2013) A review of chemical composition and nutritional value of wild-growing and cultivated mushrooms. J Sci Food Agric 93:209–218. doi:10.1002/jsfa.5960
PubMed
Kaneda T, Tokuda S (1966) Effect of various mushroom preparations on cholesterol levels in rats. J Nutr 90:371–376PubMed
Kang MG, Kim YH, Bolormaa Z, Kim MK, Seo GS, Lee JS (2013) Characterization of an antihypertensive angiotensin I-converting enzyme inhibitory peptide from the edible mushroom Hypsizygus marmoreus. Biomed Res Int 2013:283964. doi:10.1155/2013/283964
PubMedPubMedCentral
Kathiresan V, Subburaman S, Krishna AV, Natarajan M, Rathinasamy G, Ganesan K, Ramachandran M (2016) Naringenin ameliorates doxorubicin toxicity and hypoxic condition in Dalton’s lymphoma ascites tumor mouse model: evidence from electron paramagnetic resonance imaging. J Environ Pathol Toxicol 35:248–261. doi:10.1615/JEnvironPatholToxicolOncol.2016013997
Kerimkulova A et al (2011) Influence of one-year treatment with lovastatin on myocardial remodeling and ischemia in patients with coronary artery disease. Anadolu Kardiyol Derg 11:16–21. doi:10.5152/akd.2011.004
PubMed
Kim DE, Kim B, Shin HS, Kwon HJ, Park ES (2014) The protective effect of hispidin against hydrogen peroxide-induced apoptosis in H9c2 cardiomyoblast cells through Akt/GSK-3beta and ERK1/2 signaling pathway. Exp Cell Res 327:264–275. doi:10.1016/j.yexcr.2014.07.037
PubMed
Kim DO, Lee KW, Lee HJ, Lee CY (2002) Vitamin C equivalent antioxidant capacity (VCEAC) of phenolic phytochemicals. J Agric Food Chem 50:3713–3717PubMed
Kim SD et al (2008) The mechanism of anti-platelet activity of davallialactone: involvement of intracellular calcium ions, extracellular signal-regulated kinase 2 and p38 mitogen-activated protein kinase. Eur J Pharmacol 584:361–367. doi:10.1016/j.ejphar.2008.02.008
PubMed
Konno S, Alexander B, Zade J, Choudhury M (2013) Possible hypoglycemic action of SX-fraction targeting insulin signal transduction pathway. Int J Gen Med 6:181–187. doi:10.2147/IJGM.S41891
PubMedPubMedCentral
Kosanic M, Rankovic B, Dasic M (2012) Mushrooms as possible antioxidant and antimicrobial agents. Iran J Pharm Res 11:1095–1102PubMedPubMedCentral
Kozarski M et al (2015) Antioxidants of edible mushrooms. Molecules 20:19489–19525. doi:10.3390/molecules201019489
PubMed
Kozuma K, Tsuchiya S, Kohori J, Hase T, Tokimitsu I (2005) Antihypertensive effect of green coffee bean extract on mildly hypertensive subjects. Hypertens Res 28:711–718. doi:10.1291/hypres.28.711
PubMed
Kroes BH, van den Berg AJ, Quarles van Ufford HC, van Dijk H, Labadie RP (1992) Anti-inflammatory activity of gallic acid. Planta Med 58:499–504. doi:10.1055/s-2006-961535
PubMed
Laranjinha JAN, Almeida LM, Madeira VMC (1994) Reactivity of dietary phenolic-acids with Peroxyl radicals – antioxidant activity upon low-density-lipoprotein peroxidation. Biochem Pharmacol 48:487–494. doi:10.1016/0006-2952(94)90278-X
PubMed
Lau CC, Abdullah N, Shuib AS, Aminudin N (2012) Proteomic analysis of antihypertensive proteins in edible mushrooms. J Agric Food Chem 60:12341–12348. doi:10.1021/jf3042159
PubMed
Lee OH, Kim KI, Han CK, Kim YC, Hong HD (2012) Effects of acidic polysaccharides from gastrodia rhizome on systolic blood pressure and serum lipid concentrations in spontaneously hypertensive rats fed a high-fat diet. Int J Mol Sci 13:698–709. doi:10.3390/ijms13010698
PubMedPubMedCentral
Lee YG et al (2008) Src kinase-targeted anti-inflammatory activity of davallialactone from Inonotus xeranticus in lipopolysaccharide-activated RAW264.7 cells. Br J Pharmacol 154:852–863. doi:10.1038/bjp.2008.136
PubMedPubMedCentral
Liang K, Ye Y, Wang Y, Zhang J, Li C (2014) Formononetin mediates neuroprotection against cerebral ischemia/reperfusion in rats via downregulation of the Bax/Bcl-2 ratio and upregulation PI3K/Akt signaling pathway. J Neurol Sci 344:100–104. doi:10.1016/j.jns.2014.06.033
PubMed
Liu M, Du M, Zhang Y, Xu W, Wang C, Wang K, Zhang L (2013) Purification and identification of an ACE inhibitory peptide from walnut protein. J Agric Food Chem 61:4097–4100. doi:10.1021/jf4001378
PubMed
Lu WJ et al (2014) Effect of Antrodia camphorata on inflammatory arterial thrombosis-mediated platelet activation: the pivotal role of protein kinase C. Sci World J 2014:745802. doi:10.1155/2014/745802
Luo Y, Chen G, Li B, Ji B, Guo Y, Tian F (2009) Evaluation of antioxidative and hypolipidemic properties of a novel functional diet formulation of Auricularia auricula and Hawthorn. Innov Food Sci Emerg 10:215–221. doi:10.1016/j.ifset.2008.06.004
Ma Z, Ji W, Fu Q, Ma S (2013) Formononetin inhibited the inflammation of LPS-induced acute lung injury in mice associated with induction of PPAR gamma expression. Inflammation 36:1560–1566. doi:10.1007/s10753-013-9700-5
PubMed
Mao G et al (2014) Extraction, preliminary characterization and antioxidant activity of Se-enriched maitake polysaccharide. Carbohydr Polym 101:213–219. doi:10.1016/j.carbpol.2013.09.034
PubMed
Matsuura H, Asakawa C, Kurimoto M, Mizutani J (2002) Alpha-glucosidase inhibitor from the seeds of balsam pear (Momordica charantia) and the fruit bodies of Grifola frondosa. Biosci Biotechnol Biochem 66:1576–1578
Mattila P et al (2001) Contents of vitamins, mineral elements, sand some phenolic compounds in cultivated mushrooms. J Agric Food Chem 49:2343–2348. doi:10.1021/Jf001525d
PubMed
Meneses ME et al (2016) Hypocholesterolemic properties and prebiotic effects of Mexican Ganoderma lucidum in C57BL/6 mice. PLoS One 11:e0159631. doi:10.1371/journal.pone.0159631
PubMedPubMedCentral
Mercan N, Duru ME, Turkoglu A, Gezer K, Kivrak I, Turkoglu H (2006) Antioxidant and antimicrobial properties of ethanolic extract from Lepista nuda (Bull.) Cooke Ann Microbiol 56:339–344
Midoh N, Miyazawa N, Eguchi F (2013) Effects of a hot-water extract of porcini (Boletus aestivalis) mushrooms on the blood pressure and heart rate of spontaneously hypertensive rats. Biosci Biotechnol Biochem 77:1769–1772. doi:10.1271/bbb.130085
PubMed
Mori K, Kobayashi C, Tomita T, Inatomi S, Ikeda M (2008) Antiatherosclerotic effect of the edible mushrooms Pleurotus eryngii (Eringi), Grifola frondosa (Maitake), and Hypsizygus marmoreus (Bunashimeji) in apolipoprotein E-deficient mice. Nutr Res 28:335–342. doi:10.1016/j.nutres.2008.03.010
PubMed
Morigiwa A, Kitabatake K, Fujimoto Y, Ikekawa N (1986) Angiotensin converting enzyme-inhibitory triterpenes from Ganoderma lucidum. Chem Pharm Bull (Tokyo) 34:3025–3028
Morishita Y, Yoshimi N, Kawabata K, Matsunaga K, Sugie S, Tanaka T, Mori H (1997) Regressive effects of various chemopreventive agents on azoxymethane-induced aberrant crypt foci in the rat colon. Jpn J Cancer Res 88:815–820PubMed
Murcia MA, Martinez-Tome M, Jimenez AM, Vera AM, Honrubia M, Parras P (2002) Antioxidant activity of edible fungi (truffles and mushrooms): losses during industrial processing. J Food Prot 65:1614–1622PubMed
Nestel P, Fujii A, Zhang L (2007) An isoflavone metabolite reduces arterial stiffness and blood pressure in overweight men and postmenopausal women. Atherosclerosis 192:184–189. doi:10.1016/j.atherosclerosis.2006.04.033
PubMed
Nguyen AH, Gonzaga MI, Lim VM, Adler MJ, Mitkov MV, Cappel MA (2017) Clinical features of shiitake dermatitis: a systematic review. Int J Dermatol. doi:10.1111/ijd.13433
Oi S, Haneda T, Osaki J, Kashiwagi Y, Nakamura Y, Kawabe J, Kikuchi K (1999) Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells. Eur J Pharmacol 376:139–148PubMed
Pan D, Zhang D, Wu J, Chen C, Xu Z, Yang H, Zhou P (2013) Antidiabetic, antihyperlipidemic and antioxidant activities of a novel proteoglycan from ganoderma lucidum fruiting bodies on db/db mice and the possible mechanism. PLoS One 8:e68332. doi:10.1371/journal.pone.0068332
PubMedPubMedCentral
Patel S, Goyal A (2012) Recent developments in mushrooms as anti-cancer therapeutics: a review. 3. Biotech 2:1–15. doi:10.1007/s13205-011-0036-2
Pinho PG, Ribeiro B, Goncalves RF, Baptista P, Valentao P, Seabra RM, Andrade PB (2008) Correlation between the pattern volatiles and the overall aroma of wild edible mushrooms. J Agric Food Chem 56:1704–1712. doi:10.1021/jf073181y
PubMed
Poddar KH, Ames M, Hsin-Jen C, Feeney MJ, Wang Y, Cheskin LJ (2013) Positive effect of mushrooms substituted for meat on body weight, body composition, and health parameters. A 1-year randomized clinical trial. Appetite 71:379–387. doi:10.1016/j.appet.2013.09.008
PubMed
Priscilla DH, Prince PS (2009) Cardioprotective effect of gallic acid on cardiac troponin-T, cardiac marker enzymes, lipid peroxidation products and antioxidants in experimentally induced myocardial infarction in Wistar rats. Chem Biol Interact 179:118–124. doi:10.1016/j.cbi.2008.12.012
PubMed
Rao YK, Fang SH, Wu WS, Tzeng YM (2010) Constituents isolated from Cordyceps militaris suppress enhanced inflammatory mediator's production and human cancer cell proliferation. J Ethnopharmacol 131:363–367. doi:10.1016/j.jep.2010.07.020
PubMed
Robati RM, Ayatollahi A, Toossi P, Younespour S (2014) Serum angiotensin converting enzyme in Pemphigus vulgaris. Indian J Dermatol 59:348–351. doi:10.4103/0019-5154.135478
PubMedPubMedCentral
Roberfroid MB (2002) Functional foods: concepts and application to inulin and oligofructose. Br J Nutr 87(Suppl 2):S139–S143. doi:10.1079/BJNBJN/2002529
PubMed
Rodriguez de Sotillo DV, Hadley M (2002) Chlorogenic acid modifies plasma and liver concentrations of: cholesterol, triacylglycerol, and minerals in (fa/fa) Zucker rats. J Nutr Biochem 13:717–726PubMed
Rokujo T, Kikuchi H, Tensho A, Tsukitani Y, Takenawa T, Yoshida K, Kamiya T (1970) Lentysine: a new hypolipidemic agent from a mushroom. Life Sci 9:379–385PubMed
Ryu Y et al (2016) Gallic acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through regulation of JNK2 signaling and Smad3 binding activity. Sci Rep-Uk 6 doi:Artn 34790 10.1038/Srep34790
Shahrzad S, Aoyagi K, Winter A, Koyama A, Bitsch I (2001) Pharmacokinetics of gallic acid and its relative bioavailability from tea in healthy humans. J Nutr 131:1207–1210PubMed
Shih CC, Chen MH, Lin CH (2014) Validation of the antidiabetic and hypolipidemic effects of Clitocybe nuda by assessment of glucose transporter 4 and gluconeogenesis and AMPK phosphorylation in Streptozotocin-induced mice. Evid Based Complement Altern Med: eCAM 2014:705636. doi:10.1155/2014/705636
Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N, Mori M (1997) Estrogen increases in vivo leptin production in rats and human subjects. J Endocrinol 154:285–292PubMed
Sturm S, Gallmetzer K, Friedl A, Waltenberger B, Temml V, Stuppner H (2016) Laricifomes officinalis – a rich source of pharmacologically active triterpenes. Planta Med 81:S1–S381. doi:10.1055/s-0036-1596557
Sun M et al (2012) Formononetin protects neurons against hypoxia-induced cytotoxicity through upregulation of ADAM10 and sAβPPα. J Alzheimers Dis: JAD 28:795–808. doi:10.3233/jad-2011-110506
PubMed
Suzuki A, Kagawa D, Ochiai R, Tokimitsu I, Saito I (2002) Green coffee bean extract and its metabolites have a hypotensive effect in spontaneously hypertensive rats. Hypertens Res 25:99–107. doi:10.1291/Hypres.25.99
PubMed
Suzuki A, Yamamoto N, Jokura H, Yamamoto M, Fujii A, Tokimitsu I, Saito I (2006) Chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats. J Hypertens 24:1065–1073. doi:10.1097/01.hjh.0000226196.67052.c0
PubMed
Takeishi Y et al (2001) Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: comparison with acute mechanical stretch. J Mol Cell Cardiol 33:1637–1648. doi:10.1006/jmcc.2001.1427
PubMed
Tanaka M, Nakaya S, Kumai T, Watanabe M, Tateishi T, Shimizu H, Kobayashi S (2001) Effects of estrogen on serum leptin levels and leptin mRNA expression in adipose tissue in rats. Horm Res 56:98–104. doi:48099PubMed
Valverde ME, Hernandez-Perez T, Paredes-Lopez O (2015) Edible mushrooms: improving human health and promoting quality life. Int J Microbiol 2015:376387. doi:10.1155/2015/376387
PubMedPubMedCentral
VanderMolen KM et al (2017) Safety assessment of mushrooms in dietary supplements by combining analytical data with in silico toxicology evaluation. Food Chem Toxicol 103:133–147. doi:10.1016/j.fct.2017.03.005
PubMed
Velioglu YS, Mazza G, Gao L, Oomah BD (1998) Antioxidant activity and total phenolics in selected fruits, vegetables, and grain products. J Agric Food Chem 46:4113–4117. doi:10.1021/Jf9801973
Wang C, Chen Z, Pan Y, Gao X, Chen H (2017) Anti-diabetic effects of Inonotus obliquus polysaccharides-chromium (III) complex in type 2 diabetic mice and its sub-acute toxicity evaluation in normal mice. Food Chem Toxicol. doi:10.1016/j.fct.2017.01.007
Wang HP et al (2006) Mechanisms underlying biochanin A-induced relaxation of the aorta differ between normotensive and hypertensive rats. Clin Exp Pharmacol P 33:802–807. doi:10.1111/j.1440-1681.2006.04443.x
Wang CD et al (2012) Effect of a novel proteoglycan PTP1B inhibitor from Ganoderma lucidum on the amelioration of hyperglycaemia and dyslipidaemia in db/db mice. Br J Nutr 108:2014–2025. doi:10.1017/S0007114512000153
PubMed
Weng CJ, Yen GC (2010) The in vitro and in vivo experimental evidences disclose the chemopreventive effects of Ganoderma lucidum on cancer invasion and metastasis. Clin Exp Metastasis 27:361–369. doi:10.1007/s10585-010-9334-z
PubMed
Witkowska AM, Zujko ME, Mironczuk-Chodakowska I (2011) Comparative study of wild edible mushrooms as sources of antioxidants. Int J Med Mushrooms 13:335–341PubMed
Wu Q et al (2010a) Chemical characterization of Auricularia auricula polysaccharides and its pharmacological effect on heart antioxidant enzyme activities and left ventricular function in aged mice. Int J Biol Macromol 46:284–288. doi:10.1016/j.ijbiomac.2010.01.016
PubMed
Wu SJ et al (2010b) Camphoratins A-J, potent cytotoxic and anti-inflammatory triterpenoids from the fruiting body of Taiwanofungus camphoratus. J Nat Prod 73:1756–1762. doi:10.1021/np1002143
PubMedPubMedCentral
Xing DX, Liu XL, Xue CK, Huang Q, Liu ZG, Xiong L (2010) The estrogenic effect of formononetin and its effect on the expression of rats' atrium estrogen receptors. Zhong Yao Cai 33:1445–1449PubMed
Xu D, Sheng Y, Zhou ZY, Liu R, Leng Y, Liu JK (2009) Sesquiterpenes from cultures of the Basidiomycete Clitocybe conglobata and their 11 beta-Hydroxysteroid dehydrogenase inhibitory activity. Chem Pharm Bull (Tokyo) 57:433–435
Xu N et al (2017) Antioxidant and anti-hyperlipidemic effects of mycelia zinc polysaccharides by Pleurotus eryngii var. tuoliensis. Int J Biol Macromol 95:204–214. doi:10.1016/j.ijbiomac.2016.11.060
PubMed
Yahaya NFM, Rahman MA, Abdullah N (2014) Therapeutic potential of mushrooms in preventing and ameliorating hypertension. Trends Food Sci Technol 39:104–115. doi:10.1016/j.tifs.2014.06.002
Yang LY, Shen SC, Cheng KT, Subbaraju GV, Chien CC, Chen YC (2014) Hispolon inhibition of inflammatory apoptosis through reduction of iNOS/NO production via HO-1 induction in macrophages. J Ethnopharmacol 156:61–72. doi:10.1016/j.jep.2014.07.054
PubMed
Yoon KN et al (2011) Appraisal of Antihyperlipidemic activities of Lentinus lepideus in Hypercholesterolemic rats. Mycobiology 39:283–289. doi:10.5941/MYCO.2011.39.4.283
PubMedPubMedCentral
Yu S, Wu X, Ferguson M, Simmen RC, Cleves MA, Simmen FA, Fang N (2016) Diets containing shiitake mushroom reduce serum lipids and serum lipophilic antioxidant capacity in rats. J Nutr 146:2491–2496. doi:10.3945/jn.116.239806
PubMed
Zhang S, He B, Ge J, Zhai C, Liu X, Liu P (2010) Characterization of chemical composition of Agaricus brasiliensis polysaccharides and its effect on myocardial SOD activity, MDA and caspase-3 level in ischemia-reperfusion rats. Int J Biol Macromol 46:363–366. doi:10.1016/j.ijbiomac.2010.01.008
PubMed
Zhang Y, Hu T, Zhou H, Zhang Y, Jin G, Yang Y (2016) Antidiabetic effect of polysaccharides from Pleurotus ostreatus in streptozotocin-induced diabetic rats. Int J Biol Macromol 83:126–132. doi:10.1016/j.ijbiomac.2015.11.045
PubMed
Zhang Y, Wang Z, Jin G, Yang X, Zhou H (2017) Regulating dyslipidemia effect of polysaccharides from Pleurotus ostreatus on fat-emulsion-induced hyperlipidemia rats. Int J Biol Macromol 101:107–116. doi:10.1016/j.ijbiomac.2017.03.084
PubMed
Zhou X, Gong Z, Su Y, Lin J, Tang K (2009) Cordyceps fungi: natural products, pharmacological functions and developmental products. J Pharm Pharmacol 61:279–291. doi:10.1211/jpp/61.03.0002
PubMed