domain: sdv chim sde

text:
Ph. D Marc Stadler

BSc Benjarong Thongbai

Ph.D Sylvie Rapior

D Kevin

Ph.D Marc Hyde

Ph. D Stadler

Kevin D Hyde

Keywords: Hericium erinaceus, ß-glucans, erinacines, hericenones, medicinal mushroom, nerve growth factor Hericium erinaceus, an amazing medicinal mushroom Hericium erinaceus, ß-glucans, erinacines, hericenones, medicinal mushroom, nerve growth factor (NGF)

Medicinal mushrooms have become a compelling topic because the bioactive compounds they contain promise a plethora of therapeutic properties. Hericium erinaceus commonly known as "Houtou" or "Shishigashira" in China and "Yamabushitake" in Japan, has commonly been prescribed in Traditional Chinese Medicine (TCM), because its consumption has been shown to be beneficial to human health. The species is found throughout the northern hemisphere in Europe, Asia, and North America. Hericium erinaceus has been firmly established as an important medicinal mushroom and its numerous bioactive compounds have been developed into food supplements and alternative medicines. However, the correspondence of the active components that cause the observed effects is often not clear. The mushroom as well as the fermented mycelia have been reported to produce several classes of bioactive molecules, including polysaccharides, proteins, lectins, phenols, and terpenoids. Most interestingly, two classes of terpenoid compounds, hericenones and erinacines, from fruiting bodies and cultured mycelia, respectively, have been found to stimulate nerve growth factor (NGF) synthesis. In this review we examine the scientific literature to explore and highlight the scientific facts concerning medicinal properties of H. erinaceus. We provide up-to-date information on this mushroom, including its taxonomy and a summary of bioactive compounds that appear related to the therapeutic potential of H. erinaceus.

Introduction

Mushrooms have been traditionally used both as highly valued food and medicine for millennia, but only recently have scientists begun to understand molecular mechanisms and benefits of their bioactive constituents (De Silva et al. 2012a, b;[START_REF] Thawthong | Discovering and domesticating wild tropical cultivatable mushrooms[END_REF][START_REF] Wasser | Current findings, future trends, and unsolved problems in studies of medicinal mushrooms[END_REF][START_REF] Wisitrassameewong | Agaricus subrufescens: a review[END_REF]. Several classes of mushroom metabolites have been classified as effective immune boosting molecules, including proteins, polysaccharides, lipopolysaccharides, and glycoproteins (Wang et al. 2001b;[START_REF] Keong | Quantification and identification of polysaccharide contents in Hericium erinaceus[END_REF]. Mushrooms also produce and accumulate several low-molecular secondary metabolites including phenols, polyketides, and terpenes that are effective medications [START_REF] Wong | Activity of aqueous extracts of lion's mane mushroom Hericium erinaceus (Bull.: Fr.) Pers (Aphyllophoromycetideae) on the neural cell line NG108-15[END_REF][START_REF] Silva | Bioactive metabolites from macrofungi: Ethnopharmacology, biological activities and chemistry[END_REF]. For example, it has been found that mushroom phenolic compounds are outstanding antioxidants that lack mutagenic properties [START_REF] Khatua | Mushroom as the potential source of new generation of antioxidant-a review[END_REF]. Important medicinal mushrooms, e.g. Agaricus subrufescens, Ganoderma sichuanense, Grifola frondosa, Lentinula edodes, Phellinus linteus, Pleurotus ostreatus and Polyporus umbellatus have been recommended for a variety of therapeutic treatments [START_REF] Donatini | Hericium erinaceus: Properties mostly related to the secretion of neuronal growth factor[END_REF]. Recently, many studies have shown that polysaccharides from mushrooms have substantial medicinal properties and no toxic side effects, unlike many existing chemotherapeutic anticancer drugs (Lee et al. 2010a).

Edible mushrooms have therefore been used to develop alternative medicines for health care, especially as support in anti-cancer therapies [START_REF] Ramberg | Immunomodulatory dietary polysaccharides: A systematic review of the literature[END_REF]. Scientists have also screened the antimicrobial properties of mushrooms to find a solution for antibiotic drug resistance in human pathogenic microorganisms (Anke et al. 1997;[START_REF] Lindequist | The pharmacological potential of mushrooms[END_REF][START_REF] Suay | Screening of basidiomycetes for antimicrobial activities[END_REF].

In this review we focus on Hericium erinaceus, an edible-medicinal mushroom, which has a long history of use in traditional medicine in Asia and has received recent attention for its potential therapeutic and neuroprotective capabilities. The aim of this article is to gather and summarize available information on H. erinaceus, including its taxonomy, phylogeny, health promoting benefits, and medicinal properties.

Morphological characteristics and taxonomy of Hericium erinaceus

Hericium erinaceus (Bull.) Pers. 1797 is a basidiomycete belonging to the family Hericiaceae, order Russulales and class Agaricomycetes [START_REF] Kirk | Dictionary of the fungi[END_REF]). An overview on synonyms of H. erinaceus is given in Table 1. Even in the current literature, the epithet is often still being misspelt as the grammatically incorrect "erinaceum", in particular by non-specialists.

Etymology and trivial names: erinaceus literally means "hedgehog" in Latin. The name was proposed by Buillard, evidently as the fungus reminded him of this animal. This is also reflected by the German name "Igel-Stachelbart" and some English common names such as "Bearded Hedgehog" and "Hedgehog Mushroom". However, the fungus has been given many other common names, all of which are related to the conspicuous macromorphology of the basidiomes. In Japan, H. erinaceus is known as "Yamabushitake"; Yamabushi literally means "those who sleep in the mountains." In China, the mushroom goes by the name "猴頭菇", which means "lion's head," and "Houtou", which means "monkey head". This mushroom is also known as "Lion's Mane", "Monkey's Mushroom", "Bear's Head", "Hog's Head Fungus", "White Beard", "Old Man's Beard", "Pom Pom" and "Bearded Tooth" in other parts of the world.

In the mature state, H. erinaceus is easy to identify as its conspicuous basidiomes consist of numerous single, typically long, dangling, fleshy spines, that are at first white, becoming yellowish, then brownish with age. Species in the genus Hericium are distinguished macroscopically by the presence of branched vs. unbranched hymenophore structures supporting spines of various lengths, occurrence in single vs. multiple clumps, and microscopically by the presence of amyloid ornamented basidiospores [START_REF] Ginns | Hericium in North America: cultural characteristics and mating behavior[END_REF][START_REF] Harrison | The genus Hericium in North America[END_REF]. However, basidiomes of Hericium often begin to differentiate from primordia more or less as a single clump, and only develop their branches with age (Bernicchia and Gorjón 2010;Mas-Geesteranus 1971;[START_REF] Koski-Kotiranta | Hydnaceous fungi of the Hericiaceae, Auriscalpiaceae and Climacodontaceae in northwestern Europe[END_REF]. Confusion stems from the fact that the long-spined species of Hericium may have short spines (1 cm in length or less) when they are at their youngest stage. The lobed tubercle of the basidiome is pendent from a tough rooting attachment arising within a woody substrate. The context is fleshy, tough, and watery; having a hint of seafood flavor reminiscent of crab or lobster. The spines are 1-4 cm long, pendent, arranged in a beard-like manner in the basidiome. The macromorphology of H. erinaceus is usually sufficient for identification. It is however, by no means easy to differentiate certain growth forms of this species from H. coralloides, since the basidiospore sizes are highly similar in both species. As a rule, basidiomes of H. coralloides tend to be much more branched, but greatly contracted forms are known to exist in which the basidiome, instead of forming long and graceful branches, consists of a massive body, very much like that of H. erinaceus. However, host substrates can be used to aid identification, as H. coralloides is associated with conifers, whereas H. erinaceus occurs on deciduous trees.

Basidiospores of both species are short ellipsoid to subglobose, 5.5-6.8 × 4.5-5.6 µm, white in mass, warty, amyloid; basidia are 4-spored 25-40 × 5-7 µm; gloeocystidia arising in subhymenium, up to 7 µm wide, with dense contents exuding as oily appearing droplets in KOH. Hyphae of the trama are 3-20 µm in diameter, inflated or not, thick-walled, at times the lumen almost closed, interwoven, giving rise to gloeocystidia in the spines [START_REF] Harrison | The genus Hericium in North America[END_REF][START_REF] Koski-Kotiranta | Hydnaceous fungi of the Hericiaceae, Auriscalpiaceae and Climacodontaceae in northwestern Europe[END_REF][START_REF] Stamets | Notes on nutritional properties of culinary-medicinal mushrooms[END_REF].

Notably, H. erinaceus has a long history of use in Traditional Chinese Medicine in Asia, but was first described in North America. As shown in Table 1, numerous synonyms have been used in the literature to describe this species, and several varieties and formae have been described, all of which are actually referring to the same fungal species (see Table 1). Most detailed descriptions and illustrations are from European countries and H. erinaceus is also commonly reported from the southern states of America. According to GBIF (http://www.gbif.org/species/5248508) the species was also recorded from Australia, but curiously there are no records from Asia, where it is being cultivated in large quantities. Hericium species are apparently not present in Africa, where only the related genus Dentipellis Donk, which forms hydnoid, resupinate crust-like basidiomes on dead wood, seems to be extant (cf. [START_REF] Hallenberg | Species complexes in Hericium (Russulales, Agaricomycota) and a new species -Hericium rajchenbergii -from southern South America[END_REF][START_REF] Zhou | Taxonomy and phylogeny of wood-inhabiting hydnoid species in Russulales: two new genera, three new species and two new combinations[END_REF].

Hericium erinaceus is considered as a saprotroph or weak parasite. The mushroom most often occurs on dead wood, but sometimes its fruiting bodies may emanate from knotholes or cracks of living hardwoods. This might be indicative of an endophytic lifestyle. In the UK, it is usually found on the central deadwood of trunks during September to December [START_REF] Boddy | Creolophus (Hericium) cirrhatus, Hericium erinaceus and H. coralloides in England[END_REF][START_REF] Boddy | Preliminary ecological investigation of four woodinhabiting fungi of conservation concern oak polypore Piptoporus quercinus (= Buglossoporus pulvinus) and the tooth fungi Hericium/Creolophus spp[END_REF][START_REF] Boddy | Ecology of Hericium cirrhatum, H. coralloides and H. erinaceus in the UK[END_REF].

The fungus is certainly not commonly encountered in Nature. In 2003, H. erinaceus was red-listed in 13 of the 23 European countries because its natural habitats are beginning to disappear [START_REF] Govaerts | World Checklist of Arecaceae. Facilitated by the Royal Botanic Gardens[END_REF].

The fungus can also easily be discriminated from its closest relatives by molecular methods.

A set of PCR primers specific to the ITS (internal transcribed spacer) nrDNA locus of Hericium species has been developed successfully, which can be used to quickly identify H. erinaceus [START_REF] Lu | PCR-based sensitive detection of medicinal fungi Hericium species from ribosomal internal transcribed spacer (ITS) sequences[END_REF][START_REF] Parfitt | New PCR assay detects rare tooth fungi in wood where traditional approaches fail[END_REF]. The taxonomy of the genus has not changed much in the past decades and seems to be rather settled, aside from the fact that H. coralloides has also been described under several synonyms. Also, the taxonomic position of H. cirrhatum still seems unsettled. This species is considered by some mycologists to represent a separate genus and is still often being referred to as Creolophus cirrhatus. Recently, three new species were described as a new to science with phylogenetic inference, viz. H. bharengense and H. yumthangense from Himalaya, India [START_REF] Das | A new species of Hericium from Sikkim Himalaya (India) Cryptog[END_REF][START_REF] Das | Two new species of hydnoid-fungi from India[END_REF] and H. rajchenbergii from Argentina [START_REF] Hallenberg | Species complexes in Hericium (Russulales, Agaricomycota) and a new species -Hericium rajchenbergii -from southern South America[END_REF]. Table 2 gives an overview of species in the genus Hericium that were published from the 19 -20 th century. Basidiomes of H. erinaceus in the natural habitat are shown in Figs. 1a and1b.

Chemical composition of fruiting bodies vs. cultured mycelia

Numerous types of biologically active compounds from mushrooms have been demonstrated

to have pharmaceutical activities and therapeutic properties. In particular, their bioactive polysaccharides have been extensively studied for potential and existing applications in pharmaceuticals and functional foods [START_REF] Giavasis | Bioactive fungal polysaccharides as potential functional ingredients in food and nutraceuticals[END_REF][START_REF] Mizuno | Immunomodulating compounds in basidiomycetes[END_REF]. However, bioactive secondary metabolites of medicinal mushrooms that can be obtained from submerged cultures may not be produced in fruiting bodies. Monitoring of nutrient consumption, respiration and metabolite production in the culture media under controlled process conditions is critical for optimizing the process. Several studies have tried to ascertain the best conditions for growing and fruiting mushrooms so that the fungi produce higher biomass and more of the valuable bioactive metabolites. [START_REF] Cui | Production of mycelial biomass and exo-polymer by Hericium erinaceus CZ-2: Optimization of nutrients levels using response surface methodology[END_REF], [START_REF] Hu | Bioconversion of agro wastes for the cultivation of the culinary-medicinal lion's mane mushrooms Hericium erinaceus (Bull.: Fr.) Pers. and H. laciniatum (Leers) Banker (Aphyllophoromycetideae) in Taiwan[END_REF], [START_REF] Kulisic | Use of different methods for testing antioxidative activity of oregano essential oil[END_REF], Lee et al. (2010b), [START_REF] Malinowska | Biosynthesis of selenium-containing polysaccharides with antioxidant activity in liquid culture of Hericium erinaceum[END_REF] and Zhang et al. (2012b) explored the efficiency of H. erinaceus to grow on different substrates including artificial media, but also cheap substrates such as agro wastes, and tofu whey.

The fungus can be grown at large scale on inexpensive substrates, which is favorable for mass production. [START_REF] Li | Chemical compositions and macrophage activation of polysaccharides from Leon's Mane culinary-medicinal mushroom Hericium erinaceus (higher basidiomycetes) in different maturation stages[END_REF] have recently established that the state of development of the cultivated mushroom has a strong influence on the composition of the polysaccharides and hence the biological activity.

Even more striking are the different compositions of fruiting bodies and cultures with regard to their content of bioactive low-molecular metabolites. For instance, hericenones and erinacines, whose bioactivities will be treated in detail further below, are predominant in either the fruiting bodies or the mycelia of H. erinaceus [START_REF] Ma | Hericenones and erinacines: stimulators of nerve growth factor (NGF) biosynthesis in Hericium erinaceus[END_REF]. Submerged cultivation is the most promising alternative for high yields of mycelial biomass and erinacines, but not hericenones, which can so far only be obtained from the mushrooms! Many researchers have turned their attention to minimizing the fermentation time in submerged culture, while maximizing production. Recently, large-scale fermentation and use of analytical techniques such as mass spectrometry coupled with high performance liquid chromatography (HPLC-MS) and 2D-nuclear magnetic resonance (NMR) for the detection and identification of bioactive secondary metabolites have been developed [START_REF] Bills | Discovery, distribution and biosynthesis of fungal secondary metabolites[END_REF]. However, recently [START_REF] Shen | Development of an enzyme linked immunosorbent assay for detection of cyathane diterpenoids[END_REF] have developed an alternative immunological method for specific detection of the cyathane terpenoids in H. erinaceus.

In general, the bioactive metabolites from H. erinaceus and other mushrooms can be classified into a) high molecular weight compounds, such as polysaccharides, and b) low molecular weight compounds such as polyketides and terpenoids [START_REF] Kawagishi | Erinacines A, B and C strong stimulators of nerve growth factor (NGF)-synthesis from the mycelia of Hericium erinaceum[END_REF][START_REF] Ma | Hericenones and erinacines: stimulators of nerve growth factor (NGF) biosynthesis in Hericium erinaceus[END_REF][START_REF] Mizuno | Antitumor-active polysaccharides isolated from the fruiting body of Hericium erinaceum, an edible and medicinal mushroom called Yamabushitake or Houtou[END_REF]). We will furst treat these two types of compounds in general, but many of their significant bioactivities will also be discussed in detail in the chapters further below. a) Polysaccharides are found mainly in the cell walls of fungi, and they are present in large quantities (about 20% of the biomass, fide [START_REF] Dong | A ß-D-glucan isolated from the fruiting bodies of Hericium erinaceus and its aqueous conformation[END_REF]Lee et al. 2009b) in the fruiting bodies, as well as the cultured mycelium. Five different polysaccharides that showed antitumor activity were isolated from basidiomes of H. erinaceus. These are xylans, glucoxylans, heteroxyloglucans, and galactoxyloglucans [START_REF] Mizuno | Antitumor-active polysaccharides isolated from the fruiting body of Hericium erinaceum, an edible and medicinal mushroom called Yamabushitake or Houtou[END_REF]. Crude water-soluble polysaccharides were extracted and fractionated from the fruiting bodies by Lee et al. (2009b). yielding a β-1,3-branched β-1,6-glucan with a laminarin-like triple helix conformation and a molecular mass of about 13 kDa. This compound activated macrophages in the immune system. [START_REF] Jia | Structural investigation of a novel rhamnoglucogalactan isolated from the fruiting bodies of the fungus Hericium erinaceus[END_REF] isolated a heteropolysaccharide with molecular weight of 1.8 × 10 4 Da, which is composed of monosaccharides including, rhamnose, galactose, and glucose. [START_REF] Zhang | Structural elucidation of a novel fucogalactan that contains 3-O-methyl rhamnose isolated from the fruiting bodies of the fungus Hericium erinaceus[END_REF][START_REF] Zhang | Structural investigation of a novel fucoglucogalactan isolated from the fruiting bodies of the fungus Hericium erinaceus[END_REF] found a hetero-polysaccharide with a molecular weight 1.9 × 10 4 Da, which was mainly composed of fructose, galactose, and glucose, while 3-O-methyl rhamnose was determined to be a minor component. Other types of purified polysaccharides from alkaline extracts of the fruiting bodies include ß-(1-3)-linked Dglucopyranosyl residues with single galactose branches (Dong at el. 2006). Lee et al. (2009a) identified a β-1, 3-branched-β-1,2-mannan with a laminarin-like triple helix conformation from submerged mycelial cultures that is able to up regulate the functional events mediated by activated macrophages. As will be shown further below, several of these compounds possess significant biological and pharmacological activities, both in vitro and in vivo. b) Numerous low molecular secondary metabolites have recently been isolated from mycelial cultures and fruiting bodies of H. erinaceus. In general, these metabolites have a poor water solubility and their extraction requires the use of organic solvents such as methanol or ethyl acetate. Aside from the above mentioned erinacines and hericenones, this concerns, e.g. the fruiting body metabolites, erinacerins A and B (1-2), of which no sigificant biological activities are known [START_REF] Yaoita | Two new aromatic compounds from Hericium erinaceum (Bull.: Fr.)[END_REF]) (Fig. 2). Several chlorinated aromatic compounds are also known from submerged cultures of the mushroom [START_REF] Ueda | Endoplasmic reticulum (ER) stress-suppressive compounds from scrap cultivation beds of the mushroom Hericium erinaceum[END_REF]). These metabolites are well-known to exhibit nonspecific activities in biologial systems, and care should be taken that they are not present in significant amounts in the dietary supplements made from the mycelia of H. erinaceus. However, there seems to be no quality control, monitoring their occurrence. Some reactive pyranones (3-6) with cytotoxicity against HeLa S3 cells were also isolated from submerged cultures [START_REF] Kawagishi | Erinapyrones A and B from the cultured mycelia of Hericium erinaceum[END_REF][START_REF] Mizuno | Bioactive substances in Hericium erinaceus (Bull.: Fr.) Pers. and its medicinal utilization[END_REF]) (Fig. 2). A summary of studies on low molecular weight secondary metabolites and organic extracts of H. erinaceus and their miscellaneous bioactivities is given in Table 3, and the chemical structures are depicted in Figs. 2-11. Many of these compounds are being treated below in the chapters about various bioactivities of Hericium. Hericium erinaceus was selected as biotransformation model species, as it is well-known for efficient terpenoids productions of the unique cyathane type. So-called cyathadiene cyclases which do not follow the isoprene rule via intermediates of cyathane diterpenoids were also isolated from the mycelia of H. erinaceus, resulting in the characterization of cyatha-3, 12-diene (8) and its isomer (9) [START_REF] Kenmoku | Isolation of (-)cyatha-3,12-diene, a common biosynthetic intermediate of cyathane diterpenoids, from an erinacine-producing basidiomycete, Hericium erinaceum, and its formation in a cell-free system[END_REF]) (Fig. 4). Erinacine E has an unique structural feature as compared with other cyathane diterpenoids and was converted to CP-41258 (7) [START_REF] Saito | Erinacine E as a kappa opioid receptor agonist and its new analogs from a basidiomycete, Hericium ramosum[END_REF]) (Fig. 2) by using Caldariomyces fumago. Detailed studies on the biosynthesis of erinacine-like metabolites were already conducted by [START_REF] Anke | Studies on the biosynthesis of striatal-type diterpenoids and the biological activity of herical[END_REF] based on herical, a derivative of this type that was so far only found in "H. ramosum" (current name H. coralloides) but not in H. erinaceus. Some recent studies investigated Hericium growing on traditional medicinal plants. They claim that the fungus "biotransforms" active plant material, thereby attaining enhanced biological activity in the resulting extract. Other researchers are presently trying to combine preparations from mushrooms with Chinese herbs. Scoparone, for example, is a coumarin derivative found in the Chinese herb Artemisia capillaries. It activates the constitutive androstane receptor in the liver, and protects kidney functions in murine in vivo models [START_REF] Huh | Inhibitory effects of DA-9601 on ethanol-induced gastrohemorrhagic lesions and gastric xanthine oxidase activity in rats[END_REF]). An ethanol extract from H. erinaceus cultivated on Artemisia capillaries inhibited gastric mucosal damage in rats in a dosedependent-manner with an effective dose 50 (ED50) value of 22.6 mg/kg [START_REF] Choi | Antiulcerogenic activity of scoparone on HCl/ethanol-induced gastritis in Rats[END_REF]). In addition, the same extract significantly attenuated hepatic lipid deposits and reduced oxidative stress in the liver of male Sprague-Dawley rats [START_REF] Choi | Curative effects of Hericium erinaceus hypha cultivated with Artemisia capillaries (HEAC) and their primary compounds on rat liver disease[END_REF]. A methanolic extract from H. erinaceus cultured on Artemisia iwayomogi, another scoparone-containing plant was also studied for various bioactivities, including proliferation of vascular smooth muscle cells, interferon-inducing activity, and CCl4-induced acute hepatotoxicity in rats [START_REF] Lee | Inhibitory effect on aflatoxin B1-8,9-epoxide formation and anti-complementary activity of methanol extract from Hericium erinaceus cultivated with Artemisia iwayomogi[END_REF][START_REF] Choi | Inhibitory effect on proliferation of vascular smooth muscle cells and protective effect on CCl4-induced hepatic damage of HEAI extract[END_REF]. It remains unclear whether the observed effects are due to scoparone, its biotransformation products, or the genuine fungal metabolites. The same holds true for a study where a solid culture of H. erinaceus cultivated with Morus alba (white mulberry) was found to have anti-inflammatory activity, but no detailed analytical characterization was carried out (Kim et al. 2011a).

In fact, the term "biotransformation" is normally used for the conversion of a certain, defined molecule to another. In classical biotransformation protocols, which have been extremely important in biotechnology, the starting materials, as well as the end products, are very well defined by their chemical structures. This however, cannot be the case if H. erinaceus, a fungus capable of digesting lignin and cellulose, is incubated with plant material whose actual composition has not been determined. Since lignin peroxidases, manganese peroxidases and laccases and even the cellulolytic enzymes of basidiomycetes are well-known to destroy even complex and recalcitrant polymers, the fungal enzymes may modify or destroy the bioactive ingredients of the medicinal plants. Such processes should therefore be monitored very carefully by means of modern analytical chemistry, including HPLC-MS, in order to determine the composition of the "biotransformation" products.

Perhaps the least alarming scenario for patients who consume such medicines would be that the fungus (i.e., Hericium) has destroyed all the plant biomass including 100% of the active ingredients, in order to produce its own mycelia and basidiomata. This, however, could easily be determined by comparing extracts from the fungus that has been grown under regular conditions with that derived from the same strain that was cultivated on the medicinal plant material. Unfortunately, the available studies do not follow these rules. In addition, the experiments have normally been carried out at a small scale, and straightforward reproducible scale-up of the procedures to allow for provision of sufficient material in order to obtain a drug that can be reliably distributed to patients is difficult to envisage. We have therefore included these papers in our review, in particular to point out potential drawbacks and can only encourage that further research on these matters should rely on an extensive analytical characterization of the samples.

Besides secondary metabolites, some enzymes have also been isolated from the fruiting bodies, such as an amylase with a molecular mass of 55 kDa and a laccase with molecular mass of 63 kDa [START_REF] Du | An amylase from fresh fruiting bodies of the monkey head mushroom Hericium erinaceum[END_REF]Wang et al. 2014). Recently, a novel fibrinolytic metalloprotease named herinase with a molecular mass of 51 kDa was identified from the fruiting bodies [START_REF] Choi | Herinase: A novel bi-functional fibrinolytic protease from the Monkey Head mushroom, Hericium erinaceum[END_REF]. Some of these studies actually associate such enzymes with health claims. The therapeutic potential of enzymes, however, remains obscure because it is difficult to conceive how they might act in the human body, especially with regard to their allergenic potential, and whether they are not destroyed by digestion. Enzymes from Hericium might nevertheless find interesting applications in the food industry, where substances derived from edible fungi will often be regarded safe and more easily approved for industrial applications than enzymes from widely unknown organisms, or such ones with known toxic properties.

Traditional use and pharmaceutical properties

Until recently scientists have paid most attention to the therapeutic potential of medicinal mushrooms to be used as antimicrobial and antioxidant agents and as an alternative natural resource in chemo-prevention and diabetes prevention (De Silva et al. 2012a, b, 2013;[START_REF] Hiwatashi | Yamabushitake mushroom (Hericium erinaceus) improved lipid metabolism in mice fed a high-fat diet[END_REF][START_REF] Wasser | Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides[END_REF][START_REF] Yang | Hypolipiddemic effect of an exo-biopolymer produced from a submerged mycelial culture of Hericium erinaceus[END_REF]. Hericium erinaceus has been a traditional mushroom in Eastern Asia since ancient times for treating neurasthenia and general debility [START_REF] Ying | Icones of medicinal fungi from China (translated, Yuehan X)[END_REF]. The most important "modern" applications of this traditional medicinal mushroom are summarized further below.

a) Anti-tumor and immune-modulating activities

Various cancers can also possibly be treated by administering preparations based on H. erinaceus, for instance esophageal cancer, intestinal cancer, pancreatic cancers and stomach cancers.

Cancer-patients who have been treated with H. erinaceus have reported significantly fewer side effects than those associated with radiotherapy and chemotherapy.

The crude water-soluble polysaccharides of H. erinaceus have been found effective against tumor cell lines in vitro, e.g. against malignant hepatocytes (HepG2), mammary carcinoma (MCF-7), lymphoma (EL4) and esophageal cancer (EC109), see Table 4. The results indicated an anti-tumor effect of polysaccharides of H. erinaceus via activation of different immune cells, such as expression of cytokines (IL-1ß and TNF-ß) and by activation production of nitric oxide. These experiments also revealed strong anti-tumor activity mediated by activation of the c-Jun-N-terminal kinases (JNKs) that are involved in apoptosis (programmed cell death), as well as increasing intracellular doxorubicinmediated apoptotic signaling via suppression of nuclear factor kappa B (NF-B) activity (Lee and Hong 2010a). Polysaccharides derived from submerged mycelial cultures of H. erinaceus have also been recognized as potential anti-cancer agents. Moreover, several studies showed aqueous and organic extracts to have immunomodulatory effects, and the mode of action of both mentioned activities seems to be based on the same biochemical targets. [START_REF] Han | Antimetastatic and immunomodulating effect of water extracts from various mushrooms[END_REF] and Lee and Hong (2010) found that polysaccharides from aqueous extracts had anti-hepatocarcinoma activity and activated NK cells indirectly through induction of IL-12 in splenocytes [START_REF] Yim | Soluble components of Hericium erinaceum induce NK cell activation via production of interleukin-12 in mice splenocytes[END_REF]Xu et al. 1994). ß-glucans extracted from submerged mycelial culture of H. erinaceus showed significant anticancer properties in animal systems. [START_REF] Liu | Immunological study on the antitumor effects of fungus polysaccharides compounds[END_REF] reported significant effects on artificial pulmonary metastatic tumor in mice with imprinting control regions (ICRs), as well as on mice burdened with sarcoma 180 (S-180). The results showed immuno-enhancing activities by increasing the number of CD4+ cells, T lymphocytes (T cells) and macrophages, which are cytotoxic to tumor cells. The H. erinaceus glucanes had significantly higher response immunity in the test group than in the control group. The anticancer activity of an orally administered freeze dried hot water extract and a microwave extract, respectively, of H. erinaceus in Balb/c mice with CT-26 colon cancer cells intracutaneously transplanted on their backs was demonstrated by Kim et al. (2011c[START_REF] Kim | Hericium erinaceus (Lion's Mane) mushroom extracts inhibit metastasis of cancer cells to the lung in CT-26 colon cancer-transplanted mice[END_REF]. The tumor weight was significantly decreased when injected daily for 2 weeks by 38 and 41%, respectively. The results highlight immune response through increased phagocytosis of cytokines such as Tumor Necrosis Factor-α (TNF-α), interleukin-1β, and interleukin-6 that enhanced the activity of natural killer cells (NK). A significant suppression of neo-angiogenesis inside the tumor was observed, mediated by a decrease of pro-angiogenic factors, vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2), and 5-lipoxygenase (5-LOX). In addition, restoration of nitric oxide (NO) production was observed in peritoneal macrophages up to 95-98% of normal levels. Polysaccharides isolated from different species of Hericium, i.e., H. laciniatum and H. erinaceus were investigated to compare their effects on humeral immunity. Polysaccharide components were mainly glucose in H. erinaceus with enhanced increase of T cells and macrophages in mice as compared to mainly galactose in H. laciniatum (Wang et al. 2001b).

Additionally these are some studies related to anticancer and immunosuppressive activities of small molecules and organic extracts that should be mentioned in this context. Kim et al. (2011b) demonstrated that ethanolic and aqueous extracts from fruiting bodies of H. erinaceus are able to inhibit the development of tumor cell growth by introducing apoptosis and to suppress the proliferation pathway in U937 human monocytic leukemia cells via caspase 3 and caspase 9 through cytochrome P450 release from mitochondria. However, the active principles were not identified and therefore cumulative effects cannot be excluded. Recently, Erinacene D (20) showed significant antitumor activity on tumor necrosis factor alpha (TNF-α) and induced NF-kB inhibitory activity, which plays an important role in transcriptional regulation of adhesion molecules and numerous cytokines. Erinacene D was found to have NF-B inhibitory activity with an IC50 value of 9.7 µM in human keratinocytes (Li et al. 2014a) (Fig. 5). It remains to be seen whether these results can be reproduced in vivo, and the observed activity seems rather low as compared to marketed drugs and developmental candidates for cancer indications, which normally act in the low nanomolar range in similar in vitro tests.

Several studies have been carried out on toxicity of H. erinaceus and products derived from it, in order to evaluate potential side effects, or to determine the effective dosages to be employed for preclinical in vivo experiments. Aqueous extracts of H. erinaceus were devoid of significant cytotoxicity to the neuroblastoma-glioma cell line, NG108-15, and the human lung fibroblast MRC-5 [START_REF] Lai | Neurotrophic properties of the Lion's mane medicinal mushroom, Hericium erinaceus (Higher Basidiomycetes) from Malaysia[END_REF]. Toxicological studies also provided satisfactory preclinical safety evidence to launch clinical trials in rats via doses of up to 5000 mg/kg/day body weight of "MUNOPHIL" a preparation comprising a mixture of aqueous extracts of H. erinaceus and Panax ginseng [START_REF] Park | Toxicological study on MUNOPHIL, water extract of Panax ginseng and Hericium erinaceum in rats[END_REF]). In addition, a toxicological safety study of erinacine A, the major active ingredient from cultures of the fungus, has been performed in a 28-day oral administration study in Sprague-Dawley rats. All animals survived, and neither developmental abnormalities nor adverse urine analysis were observed (Choi et al. 2011;Li et al. 2014b). Chemotherapy is the main treatment for patients with cancer, but the toxicity is extensive. Fluorouracil (5-FU) is a chemotherapeutic drug used to treat several types of cancer. Hericium erinaceus extracts have shown potential in treating gastrointestinal cancer, during both in vivo and in vitro experiments that was superior to that of 5-FU (Li et al. 2014a). The standard drug was less efficient and more toxic than the fungal samples.

In summary, these results appear promising, but notably, there is no anticancer drug based on Hericium on the market yet because clinical efficacy studies have not been conducted.

b) Metabolic syndromes: antihyperglucemic and antihypercholesterolemic activities

Mushrooms provide a healthy food source as they are rich in proteins, vitamins, fibers and minerals and low in carbohydrates, but contain low amounts of fat and cholesterol [START_REF] Lau | Proteomic analysis of antihypertensive proteins in edible mushrooms[END_REF][START_REF] Phillips | Vitamin D and sterol composition of 10 types of mushrooms from retail suppliers in the United States[END_REF][START_REF] Thawthong | Discovering and domesticating wild tropical cultivatable mushrooms[END_REF][START_REF] Ulziijargal | Nutrient compositions of culinary medicinal mushroom fruiting bodies and mycelia[END_REF]. Some species are therefore used as functional foods with anti-diabetic effects or for dietetic prevention of cardiovascular diseases, which are one of the major causes of death in both western and Asia-Pacific countries [START_REF] Ali | Characteristics associated with poor glycemic control among adults with self-reported diagnosed diabetes-National health and nutrition examination survey, United States, 2007-2010[END_REF]. Diabetes mellitus is a group of metabolic diseases with abnormal production of insulin and/or insulin dysfunction, recognized by high blood glucose (hyperglycemia) (De Silva et al. 2012b, 2013). Several studies have determined antihypoglycemic activities in fruiting bodies and mycelium from numerous medicinal mushrooms [START_REF] Hikino | Mechanisms of hypoglycemic activity of ganoderan B: A glycan of Ganoderma lucidum fruit bodies[END_REF][START_REF] Sato | Dehydrotrametenolic acid induces preadipocyte differentiation and sensitizes animal models of noninsulin-dependent diabetes mellitus to insulin[END_REF][START_REF] Teng | Hypoglycemic effect and mechanism of a proteoglycan from Ganoderma lucidum on streptozotocin-induced type 2 diabetic rats[END_REF][START_REF] Badole | Hypoglycemic activity of aqueous extract of Pleurotus pulmonarius in alloxan-induced diabetic mice[END_REF]). The potential anti-hyperglycemia effect of extracts from fruiting bodies and mycelia of H. erinaceus has also been reported in diabetic animals. [START_REF] Vertesy | Novel phthalaldehyde derivatives, process for their preparation, and their use CA[END_REF] tested the phthalaldehyde derivatives, hericenals A (21), B ( 22) and C (23) from submerged cultures for therapeutic treatment of Diabetes mellitus in particular disorders of glucose metabolism or other metabolic disorders of the human body. Furthermore, exo-polymers isolated from submerged cultures have shown beneficial effects in hypoglycemic rats by oral administration [START_REF] Yang | Hypolipiddemic effect of an exo-biopolymer produced from a submerged mycelial culture of Hericium erinaceus[END_REF]) (Fig. 6).

D-threitol, D-arabinitol and palmitic acid and α-D-glucan are major components from fruiting bodies of H. erinaceus that also have demonstrated antihyperglycemic effects in diabetic rats [START_REF] Wang | Hypoglycemic effect of extract of Hericium erinaceus[END_REF][START_REF] Hiwatashi | Yamabushitake mushroom (Hericium erinaceus) improved lipid metabolism in mice fed a high-fat diet[END_REF]). These components also showed significant anti-hypercholesterolemic effects and reduced the plasma total cholesterol, LDL cholesterol, triglycerides, phospholipid, atherogenic index and hepatic HMG-CoA reductase activity. Rats given an oral administration of extract of H. erinaceus had increased plasma HDL cholesterol levels as compared to the control group fed with saline [START_REF] Yang | Hypolipidemic effect of exo-polymer produced in submerged mycelial culture of five different mushrooms[END_REF][START_REF] Yang | Hypolipiddemic effect of an exo-biopolymer produced from a submerged mycelial culture of Hericium erinaceus[END_REF][START_REF] Wang | Hypoglycemic effect of extract of Hericium erinaceus[END_REF].

Several studies have demonstrated significant anti-hyperglycemic and anti-hyperlipidemic effects in streptozotocin-induced diabetic rats fed with methanol and acqueous extracts of H. erinaceus [START_REF] Wang | Hypoglycemic effect of extract of Hericium erinaceus[END_REF][START_REF] Liang | Antihyperglycemic and antihyperlipidemic activities of aqueous extract of Hericium erinaceus in experimental diabetic rats[END_REF]. Significantly lower elevation rates of blood glucose level and increased serum insulin level occurred in rats fed with HEM, as compared with untreated control groups. In another study, the mycelial ethanol extract of the mushrooms, significantly reduced serum content of low density lipoprotein-cholesterol (LDL-C) by 45.5% and effectively increased high density lipoprotein-cholesterol (HDL-C) by 31.1% in serum of diabetic mice [START_REF] Yang | Hypolipiddemic effect of an exo-biopolymer produced from a submerged mycelial culture of Hericium erinaceus[END_REF]. In a similar study, ethanol extracts of H. erinaceus showed hypoglycemic action, which might affect activation of peroxisome proliferator-activated receptor alpha (PPARα) at EC50 = 40 µg/ml and could regulate lipid metabolic gene expression of C57BL/6 in mice with Diabetes mellitus [START_REF] Hiwatashi | Yamabushitake mushroom (Hericium erinaceus) improved lipid metabolism in mice fed a high-fat diet[END_REF]. Even though clinical studies on humans are not yet available, the above studies indicate the great potential of H. erinaceus to treat metabolic disorders and prevent cardiovascular diseases.

The methanolic mycelial extracts of the fungus also showed protective effect on CCl4-induced hepatic damage [START_REF] Choi | Inhibitory effect on proliferation of vascular smooth muscle cells and protective effect on CCl4-induced hepatic damage of HEAI extract[END_REF]. It remains unclear whether the hydrophilic macromolecules or the more lipophilic secondary metabolites are responsible for this effect.

c) Neuroprotective activity

The Nerve growth factor (NGF) is a highly conserved protein critical for survival that is involved in preventing neuronal death and promoting neuritis outgrowth, supporting synapse formation, and enhancing memory function, and is also essential in maintaining and organizing neuron function [START_REF] Obara | The signaling pathway of neurotrophic factor biosynthesis[END_REF]. Rita Levi-Montalcini and Stanley Cohen were awarded the 1986 Nobel Prize in Physiology/Medicine for discovering the NGF. The authors discovered an important biological effect of nerve growth factor on neuronal cells and on several non-neuronal cells and explained the possible mechanism of Nerve growth factor on cells of the immune system (Levi-Montalcini 1996; Aloe 2004).

It is assumed that functional deficiency of Nerve growth factor is related to Alzheimer's disease (AD) and is expected to be applied to the treatment of Alzheimer's disease patients [START_REF] Allen | Clinical relevance of the neurotrophins and their receptors[END_REF]. AD is a progressive neurodegeneration of the brain that is commonly diagnosed in the aging population over 65 years old and women have higher risk of this kind of disease [START_REF] Shen | Brain cholinesterases: II The molecular and cellular basis of Alzheimer's disease[END_REF][START_REF] Prine | World Alzheimer report 2014 -dementia and risk reduction an analysis of protective and modifiable factors[END_REF]. AD is identified in patients by synaptic injury deficiency of neurotransmitters, unfunctioning and/or death of neural cells, and possibly by interference with the process of adult neurogenesis in the hippocampus [START_REF] Crews | Molecular mechanisms of neurodegeneration in Alzheimer's disease[END_REF]. AD patients have abnormal accumulation of amyloid-ß peptide containing neurofibrillary tangles composed of hyperphosphorylated tau proteins. (Murphy and Levine 2010). Symptoms of Alzheimer's disease include confusion, memory forming loss and behavior changes. Neurotrophic factors are essential for maintenance and organization of neurons functionally. Hence, neurotrophic factor-like substances or their inducers are expected to be applied to cure neurodegenerative diseases such as AD. In addition, it is estimated that over 5 million Americans live with AD and this number will increase by an average of 50% by the year 2025 [START_REF] Anonymous | Alzheimer's Association: Alzheimer's disease -facts and figures[END_REF][START_REF] Gaugler | Alzheimer's Disease facts and figures[END_REF]World Alzheimer Report 2014).

However, the efficacy of current drugs for the treatment of Alzheimer's disease patients is still unclear.

The endoplasmic reticulum is one of the important organelles triggering a specific program of cell death via induced apoptotic pathways with a signaling between ER and mitochondria and therefore also constitutes a valid target for neuroprotective drugs [START_REF] Ueda | An endoplasmic reticulum (ER) stress-suppressive compound and its analogues from the mushroom Hericium erinaceum[END_REF]. Endoplasmic reticulum stress causes brain cells to die which leads to development of neurodegenerative diseases.

Dilinoleoyl-phosphatidylethanolamine (DLPE) isolated from H. erinaceus appears to reduce endoplasmic reticulum stress and amyloid-β peptide (A-β ) toxicity by decreasing neuronal cell death of Neuro2a cells via the protein kinase C pathway [START_REF] Nagai | Dilinoleoyl-phosphatidylethanolamine from Hericium erinaceus protects against ER stress-dependent Neuro2a cell death via protein kinase C pathway[END_REF]. Another strongly bioactive compound named 3-hydroxyhericenone (29a), showed protective activity against neuronal cell death of Neuro-2a caused by endoplasmic reticulum stress [START_REF] Ueda | An endoplasmic reticulum (ER) stress-suppressive compound and its analogues from the mushroom Hericium erinaceum[END_REF]. Furthermore, the Functional Independence Measure (FIM) score regarding disease progression of preliminary clinical trials showed improvement in patients with dementia [START_REF] Kawagishi | Compounds for dementia from Hericium erinaceum[END_REF].

Myelin sheaths wrap neuronal axons and play important functions in the support and speed up the neural signal. Hence, injury of the myelin structure leads to an impairment and severe illness of the nerve system. Hericium erinaceus shows an action on the nerve tissue in vitro assay. Extracts from H. erinaceus showed abilities to promote normal development of cultivated cerebellar cells and demonstrated a regulatory effect on the process of myelin genesis [START_REF] Kolotushkina | The influence of Hericium erinaceus extract on myelination process in vitro[END_REF]. Many studies worldwide have reported that H. erinaceus may be appropriate for the prevention or treatment of dementia diseases. Organic extracts from fruiting bodies of H. erinaceus demonstrated neurotrophic effects enhancing the myelination process in the mature myelinating fibers in vitro assays [START_REF] Moldavan | Neurotropic and trophic action of lion's mane mushroom Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) extracts on nerve cells in vitro[END_REF]). [START_REF] Mori | Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells[END_REF] reported that ethanol extracts of H. erinaceus can stimulate nerve growth factor synthesis via activation of the c-Jun N-terminal kinases (JNKs) pathway, in a concentration-dependent manner, by enhancing the nitrite outgrowth of PC12 cells in 1321N1 human astrocytoma. [START_REF] Mori | Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: A double-blind placebocontrolled clinical trial[END_REF] found significant prevention of cognitive impairment with H. erinaceus powder from air-dried fruit bodies. A double-blind, parallel-group, placebocontrolled clinical study was performed with oral administration of H. erinaceus on 50-80 year old individuals with mild cognitive impairment. The group treated with H. erinaceus showed significantly increased scores on the cognitive function scale compared with the placebo group. Dietary administration of 96% H. erinaceus powder 250 mg tablets also resulted in prevention of dementia and decreased cognitive impairment of spatial short term and memory deficits in ICR mice induced by amyloid-β peptide [START_REF] Mori | Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: A double-blind placebocontrolled clinical trial[END_REF]. Oral administrations of the aqueous extract from fruiting bodies of H. erinaceus promoted regeneration of injured adult female Sprague-Dawley rat nerve-injury during the early stage of recovery (Wong et al. 2009a;[START_REF] Wong | Peripheral nerve regeneration following crush injury to rat peroneal nerve by aqueous extract of medicinal mushroom Hericium erinaceus (Bull.: Fr) Pers. (Aphyllophoromycetideae)[END_REF].

Nerve growth factor is easily metabolized by peptidases and is also unable to cross the bloodbrain barrier. Therefore, the low molecular weight compounds of H. erinaceus such as hericenones and erinacines were investigated for significant bioactivities that increase mRNA expression of Nerve growth factor biosynthesis. Hericenones and erinacines are low-molecular weight compounds that can easily cross the blood-brain barrier [START_REF] Moldavan | Neurotropic and trophic action of lion's mane mushroom Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) extracts on nerve cells in vitro[END_REF][START_REF] Kawagishi | Compounds for dementia from Hericium erinaceum[END_REF][START_REF] Kim | a) Immunomodulatory and anti-inflammatory activity of mulberry (Morus alba) leaves fermented with Hericium erinaceum mycelium by solid-state culture. Han'guk Sikp'um Yongyang[END_REF]).

However, the detailed mechanism by which erinacines and hericenones induces Nerve growth factor biosynthesis remains unknown. Hericenones and erinacines had neurotrophic, but not neuroprotective activities when applied in combination of 10 ng/mL NGF with 1 μg/mL H. erinaceus extracts.

Hericium erinaceus contained neuroactive compounds that showed the highest percentage increase of 60.6% on neurite outgrowth stimulation and induced Nerve growth factor synthesis in neuroblastomaglioma cell line NG108-15 [START_REF] Kenmoku | Isolation of (-)cyatha-3,12-diene, a common biosynthetic intermediate of cyathane diterpenoids, from an erinacine-producing basidiomycete, Hericium erinaceum, and its formation in a cell-free system[END_REF][START_REF] Lai | Neurotrophic properties of the Lion's mane medicinal mushroom, Hericium erinaceus (Higher Basidiomycetes) from Malaysia[END_REF].

Hericenones A (24) and B (25) were originally isolated from the fruiting bodies of H. erinaceus and showed significant cytotoxicity against HeLa cells (Kawagishi et al. 1990a).

Hericenones C (27), D (28), E (29) and H (31) exhibited stimulating activity in the synthesis of Nerve growth factor in vitro. The hericenones F (30) and G did not stimulate Nerve growth factor synthesis under the same conditions [START_REF] Kawagishi | Hericenones C, D and E, stimulators of nerve growth factor (NGF)-synthesis from the mushroom Hericium erinaceum[END_REF][START_REF] Kawagishi | Chromans, hericenones F, G and H from the mushroom Hericium erinaceum[END_REF][START_REF] Mizuno | Bioactive substances in Hericium erinaceus (Bull.: Fr.) Pers. and its medicinal utilization[END_REF]. Furthermore, hericenones I (32), J (33) and L were also identified, and hericenone L showed cytotoxic activity against EC109 tumor cells [START_REF] Ma | Hericenone L, a new aromatic compound from the fruiting bodies of Hericium erinaceum[END_REF]) (Fig. 7). There is debate as to whether hericenones are active components stimulating biosynthesis of Nerve growth factor. Other studies have reported that hericenones C and D do not increase Nerve growth factor biosynthesis in cell line 1321N1 [START_REF] Mori | Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells[END_REF]. Hericenone E was able to stimulate Nerve growth factor synthesis in rat pheochromocytoma (PC12) cells when investigated using several pharmacological inhibitors. Hericenone E was able to stimulate Nerve growth factor secretion which was two-fold higher than that of the positive control (50 ng mL -1 of NGF) and increased phosphorylation on mitogen-activated protein kinases or extracellular signalregulated kinases (MEK/ERKs) pathway and also increased protein kinase B (PKB) [START_REF] Phan | Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways[END_REF]).

Erinacine derivatives are potential medicines for degenerative neuronal disorders and peripheral nerve regeneration. Several erinacines from submerged culture with unique ability to promote activity of Nerve growth factor synthesis have already been found. Erinacines A (34), B (35), C (36), D (37), E (38) F (39), G (40), H (41), and I (42) showed a stronger biological activity that stimulates Nerve growth factor synthesis than epinephrine used as a positive control on murine astroglial cells [START_REF] Kawagishi | Erinacines A, B and C strong stimulators of nerve growth factor (NGF)-synthesis from the mycelia of Hericium erinaceum[END_REF](Kawagishi et al. , 1996a(Kawagishi et al. , 1996b;;[START_REF] Lee | Two novel diterpenoids, erinacines H and I from the mycelia of Hericium erinaceum[END_REF] (Fig. 8). All these diterpenoids possess a cyathane skeleton consisting of angularly condensed five-, six-, and seven-membered rings.

Additionally, erinacine A significantly increased the level of Nerve growth factor in the rat's locus caeruleus and hippocampus, but not in the cerebral cortex in an oral administration study [START_REF] Shimbo | Erinacine A increases catecholamine and nerve growth factor content in the central nervous system of rats[END_REF]. A cyathane-xyloside, erinacine P (43) and its biomimetic conversions into erinacine A and erinacine B, was also found to induce the Nerve growth factor -syntheses compared with epinephrine as a positive control [START_REF] Kenmoku | Isolation of erinacine P, a new parental metabolite of cyathanexylosides from Hericium erinaceus and its biomimetic conversion into erinacines A and B[END_REF] (Fig. 9). [START_REF] Kenmoku | Erinacine Q, a new erinacine from Hericium erinaceus, and its biosynthetic route to erinacine C in the basidiomycete[END_REF] isolated erinacine Q (44) and its biosynthetic route to erinacine C. A cyatha-3,12-dien-14-β-ol named erinacol (45) and 11-O-acetylcyathin A3 (46), both of which are probably biosynthetically related to erinacine Q were isolated by [START_REF] Kenmoku | Erinacol (cyatha-3,12-dien-14β-ol) and 11-O-acetylcyathin A3, new cyathane metabolites from an erinacine Q-producing Hericium erinaceum[END_REF] and also reported to have Nerve growth factor -enhancing activities. The stereochemistry of erinacine R (47) was elucidated by Ma et al. 2008 (Fig. 9). Several studies were conducted on the mechanisms involved in the neuroprotection process of the brain from extracts from H. erinaceus [START_REF] Hazekawa | Neuroprotective effect of repeated treatment with Hericium erinaceum in mice subjected to middle cerebral artery occlusion[END_REF][START_REF] Mori | Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells[END_REF][START_REF] Mori | Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: A double-blind placebocontrolled clinical trial[END_REF][START_REF] Phan | Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways[END_REF]. [START_REF] Lee | Protective effects of Hericium erinaceus mycelium and its isolated erinacine A against ischemia-injury-induced neuronal cell death via the inhibition of iNOS/p38 MAPK and nitrotyrosine[END_REF] found the effects of erinacine A, which is capable of preventing ischemic injury to neurons; possibly act as an anti-inflammatory agent to bring about neuroprotection using a model of global ischemic stroke and the mechanisms involved.

Rats were treated with erinacine A. The extracts reduced the total infracted volumes by 22% and 44% at a concentration of 50 and 300 mg/kg, by oral administration of erinacine A, respectively, compared to the stroke animal model group. Erinacine A showed potent nerve-growth enhancing properties and effectively inhibited neuronal cell death via reduced levels of nitrotyrosine-containing proteins, phosphorylation of p38 MAPK and CCAAT enhancer-binding protein (C/EBP) and homologous protein (CHOP).

Investigations of the effectiveness of the bioactive compounds based on clinical trials in patients are now receiving much attention in Asia, e.g., China, Japan, Korea, and Malaysia. Specifically, these reports support promising potential of hericenones and erinacines that enhance Nerve growth factor synthesis. However further studies need to determine the mechanism of hericenones and erinacines whether the compounds are able to stimulate Nerve growth factor in the brain in vivo. Furthermore, clinical trials of patients treated with extracts of H. erinaceus indicated a significant effect on reduced depression and anxiety in 30 randomly selected females. Examples of clinical trials of patients treated with hericenones and erinacines from H. erinaceus are listed in Table 5.

d) Antimicrobial activity

Medicinal mushrooms are rich sources of secondary metabolites with activity against a wide range of microorganisms including bacteria, yeasts and filmentous fungi. These substances include diterpenoids, such as pleuromutilin from the genus Clitopilus, which led to the discovery of the marketed drug retapamulin [START_REF] Kilaru | Establishing molecular tools for genetic manipulation of the pleuromutilin-producing fungus Clitopilus passeckerianus[END_REF]). Other antibiotics have been isolated from Ganoderma [START_REF] Richter | An assessment of the taxonomy and chemotaxonomy of Ganoderma[END_REF]) and many other species. It is hoped that further research on antimicrobial agents from basidiomycetes will lead to alternative antibiotic drugs on the market [START_REF] Silva | Bioactive metabolites from macrofungi: Ethnopharmacology, biological activities and chemistry[END_REF][START_REF] Stadler | Fungal natural products-the mushroom perspective[END_REF]. Even H erinaceus has been shown to be a source of a number of antimicrobial agents. Phenol-like and fatty acid-like compounds from the extracts of H. erinaceus were shown to have antifungal and antibacterial activity. 4-Chloro-3,5-dimethoxybenzyl alcohol, 4chloro-3,5-dimethoxylbenzaldehyde and chlorinated orcinol from mycelial extracts possessed antimicrobial activity [START_REF] Okamoto | Antimicrobial chlorinated orcinol derivatives from mycelia of Hericium erinaceum[END_REF]. The submerged cultures contained hericene A (48), B (49), C (50) and erinapyrone C (51), which showed moderate bioactivities against Gram-positive bacteria [START_REF] Rosanna | Secondary mold metabolites: part 46. Hericenes A-C and erinapyrone C: new metabolites produced by the fungus Hericium erinaceum[END_REF][START_REF] Kawagishi | Erinapyrones A and B from the cultured mycelia of Hericium erinaceum[END_REF]) (Fig. 10).

In the 2000's other antimicrobial compounds from H. erinaceus were reported to be active against fungi, and protozoa, as well as various pathogenic gram-positive and gram-negative bacteria [START_REF] Lindequist | The pharmacological potential of mushrooms[END_REF]Wong et al. 2009b). Methicillin-resistant Staphylococcus aureus (MRSA) is a gram-positive bacterium that currently causes illness worldwide. The mycelium extract of H. erinaceus exhibited a minimal inhibitory concentration (MIC) with EC50value of 5.5 µl/ml against Staphyloccocus aureus [START_REF] Kim | Isolation of antimicrobial substances from Hericium erinaceum[END_REF]. Furthermore, cyathane derivatives named erinacines J ( 52) and K (53) were tested for their effectiveness against MRSA. Only erinacine K showed anti-MRSA activity in the direct drop and minimum inhibitory concentration (MIC) bioassays. This was attributed due to chemical substitutions present in the three-ring skeleton of the aglycon in biologically active compounds expressing anti-MRSA activity [START_REF] Kawagishi | Anti-MRSA Compounds from Hericium erinaceus (Bull.:Fr.)[END_REF][START_REF] Kawagishi | Erinacines J and K from the mycelia of Hericium erinaceum[END_REF]) (Fig. 10).

In clinical tests conducted by the Japanese group, MRSA were reported to have disappeared in a percentage of patients whose diet was supplemented with extracts of both fruiting body and mycelium of H. erinaceus [START_REF] Kawagishi | Anti-MRSA Compounds from Hericium erinaceus (Bull.:Fr.)[END_REF]).

More recently, Kim et al. (2012) metabolites from the fruiting body of H. erinaceus with effective antimicrobial activity in an in vivo assay against the growth of Salmonella via stimulation of the immune system. A direct inhibitory effect of ethanol and ethyl acetate extracts of H. erinaceus fruiting bodies against Helicobacter pylori was found in patients associated with chronic gastritis and gastric ulcers [START_REF] Shang | In vitro anti-Helicobacter pylori effects of medicinal mushroom extracts, with special emphasis on the Lion's Mane mushroom, Hericium erinaceus (higher Basidiomycetes)[END_REF]. Several studies indicate that extracts of biologically active compounds from H. erinaceus possess significant anti-microbial effects that could be improved for pharmacological properties. Even the immunomodulatory effect of secondary metabolites mentioned above could help to overcome bacterial infections by boosting the immune system of the human host.

e) Antioxidant and anti-ageing activities

Reactive oxygen species (ROS) derived from oxygen can cause oxidative stress which leads to a variety of diseases including cancer, Alzheimer's disease (AD), cardiovascular disease, and the aging process [START_REF] Ames | Oxidants, antioxidants and the degenerative diseases of aging[END_REF][START_REF] Halliwell | Free radicals and antioxidants: updating a personal view[END_REF]. This mechanism can produce free radicals or various reaction oxygen species capable of damaging tissues, and functional cell components such as DNA, protein and lipids of host organisms. Antioxidant molecules are beneficial as they inhibit oxidation reactions and eliminate free radicals [START_REF] Krishnaiah | A review of the antioxidant potential of medicinal plant species[END_REF][START_REF] Valko | Free radicals and antioxidants in normal physiological functions and human disease[END_REF]).

Many studies have been carried out to investigate antioxidant properties of H. erinaceus [START_REF] Abdullah | Evaluation of selected culinary medicinal mushrooms for antioxidant and ACE inhibitory activities[END_REF][START_REF] Fu | Antioxidant and free radical scavenging activities of edible mushrooms[END_REF][START_REF] Malinowska | Biosynthesis of selenium-containing polysaccharides with antioxidant activity in liquid culture of Hericium erinaceum[END_REF][START_REF] Mau | Antioxidant properties of several specialty mushrooms[END_REF][START_REF] Mujić | Antioxidant properties of selected edible mushroom species[END_REF]). An investigation of phenolics from mycelium extracts in hot water of H. erinaceus has been reported to evaluate the in vitro antioxidant by [START_REF] Abdullah | Evaluation of selected culinary medicinal mushrooms for antioxidant and ACE inhibitory activities[END_REF]. The Folin-Ciocalteu method used to estimate the total phenolics, being expressed as gallic acid equivalents (GAEs) that reflected the phenolic content as the amount of gallic acid (mg) in 1 g of extract [START_REF] Ferreira | Antioxidants in wild mushrooms[END_REF]).

Another study reported on the antioxidant properties of phenolic compounds from fruiting bodies and mycelia. Mycelial extracts contained the highest total phenolic content and the highest ferric reducing antioxidant power (FRAP). Both fresh and oven-dried fruiting body extracts contained phenolic compounds with antioxidant activities. However, possibly due to the generation and accumulation of Maillard's reaction products (MRPs) during the dry processing, the potential antioxidant capacity of oven-dried fruiting bodies was higher than the freeze-dried extract (Wong et al. 2009b).

The lipopolysaccharides (LPS) from mycelia showed significant anti-oxidative activities in BALB/C mice through the elevation of hepatic glutathione levels [START_REF] Jang | Effect of Hericium erinaceus mycelia supplementation on the oxidative stress and inflammation processes stimulated by LPS and their mechanisms in BALB/C mice[END_REF]. [START_REF] Han | Evaluation of in vivo antioxidant activity of Hericium erinaceus polysaccharides[END_REF] showed significant antioxidant activity against ischemia reperfusion induced renal oxidative injury damage in mice. The results of pre-administration of the β-glucans from H. erinaceus showed increased antioxidant enzymes activities as well as decreased lipid peroxidation levels. Zhang et al.

(2012a) isolated endo-polysaccharides from ethanolic mycelium extracts of H. erinaceus grown on tofu whey that exhibited extremely high antioxidant effect in vitro assays. These results suggested that H. erinaceus extracts can be a good source for increasing antioxidant enzyme activities in humans. [START_REF] Xu | Chemical analysis of Hericium erinaceum polysaccharides and effect of the polysaccharides on derma antioxidant enzymes, MMP-1 and TIMP-1 activities[END_REF] also found that β-glucanes from H. erinaceus showed significant anti-skin aging properties, due inhibition of matrix metalloproteinase (MMP)-1, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 activities in aged rat models. These date, however, were so far not corroborated by activities during in-vivo experiments.

f) Other therapeutic uses and biological activities of Hericium metabolites

Different bioactive metabolites derived from H. erinaceus are supposed to be safe to be used as pharmaceutical products and dietary supplements due to the minimum side effects of compounds of natural origin. Most of the potential properties of H. erinaceus extracts from fruiting bodies have been studied in animal models for nearly three decades. The cytoprotective effects of H. erinaceus freeze dried fruiting bodies have been shown to be effective against ethanol-induced gastric mucosal injury in rats [START_REF] Abdulla | Effect of culinary medicinal lion's mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) on ethanol induced gastric ulcers in rats[END_REF]). In addition, the aqueous extract from fruiting bodies of H. erinaceus enhanced the acceleration of wound healing in experimentally wounded and dressed male Sprague-Dawley rats [START_REF] Abdulla | Potential activity of aqueous extract of culinary medicinal Lion's Mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) in accelerating wound healing in rats[END_REF]. Hericium erinaceus can be useful in patients who are suffering from gastric ulcers as well as those of the oesophagus and appear to suppress and prevent Crohn's disease, characterized by the inflammation of the gut walls [START_REF] Abdulla | Effect of culinary medicinal lion's mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) on ethanol induced gastric ulcers in rats[END_REF][START_REF] Wong | Gastroprotective effects of lion's mane mushroom Hericium erinaceus (Bull.:Fr.) Pers. (Aphyllophoromycetideae) extract against ethanol-induced ulcer in rats[END_REF].

A Hericium erinaceus extract was investigated for acute respiratory distress syndrome in a case study of a 63-year-old man who was admitted to the hospital for intensive care of severe acute respiratory failure with diffuse infiltration in both lungs. Lymphocytes stimulation test showed a strong reactivity against H. erinaceus extract daily for four months [START_REF] Nakatsugawa | Hericium erinaceus (Yamabushitake) extract-induced acute respiratory distress syndrome monitored by serum surfactant proteins[END_REF].

Inhibitors of platelet aggregation are preventive or therapeutic agents of various vascular diseases, including myocardial infarction and stroke, as platelet aggregation in the blood vessel causes thrombosis. The bioactive activity of hericenone B from fruiting body also exerts anti-platelet action.

Hericenone B showed stimulating activity releasing of arachidonic acid as mediates receptor thrombosis via collagen through α2/β1 in tested rabbit. Specifically, only hericenone B showed inhibition of collagen-induced platelet aggregation when compared with hericenone C, D and E with inhibition at 30 µM similar to 5 µM aspirin as a reference investigated in vivo [START_REF] Farndale | The role of collagen in thrombosis and hemostasis[END_REF][START_REF] Mori | Inhibitory effect of hericenone B from Hericium erinaceus on collagen-induced platelet aggregation[END_REF].

Hericium erinaceus also contained a biologically active substance which showed activities on plant-growth. Hericerin (54), for instance, showed activity against pine pollen germination and tea pollen growth [START_REF] Kimura | Hericerin, a new pollen growth inhibitor from the mushroom Hericium erinaceum[END_REF]) (Fig. 11). The recently isolated erinaceolactones A (55), B (56) and C (57) isolated from fruiting bodies have shown plant-growth regulatory activity [START_REF] Wu | Erinaceolactones A to C, from the culture broth of Hericium erinaceus[END_REF] (Fig. 11).

5-. Hericium erinaceus containing products

Scientists have established the components of medicinal mushrooms, including various polysaccharides, such as lentinan from Lentinula edodes, ganoderic acids from Ganoderma lucidum, polysaccharopeptide krestin (PSK) in Trametes versicolor, and a protein-bound polysaccharide complex in Macrocybe lobayensis. [START_REF] Hyde | Fungi -an unusual source for cosmetics[END_REF] also reported on some cosmetics containing mushroom products, made from A. subrufescens as the main bioactive ingredient. Recently, numerous commercial medicinal products and nutritional food with pharmaceutical properties have been derived from medicinal mushrooms. Biologically active compounds isolated from other fungi could provide a novel kind of cosmeceuticals with significant immune enhancement. Almost all pharmaceutical products have been derived from commercial fruiting bodies, as compared to those extracted from mycelia, approximately 80-85% vs. 15%, respectively. Gastric cancer is the second most common cancer worldwide. In the United States (US) the National Cancer Institute documented a significant increase of about 25% in all common cancer forms of gastrointestinal (GI) cancers such as liver, gastric and colorectal cancers in recent years [START_REF] Anand | Cancer is a preventable disease that requires major lifestyle changes[END_REF]Dicken et al.2005). It is appears likely that the culture extracts of H. erinaceus processed into medications have been brought into production on a large scale, mainly for healing chronic gastricism and gastric-cancer [START_REF] Li | A novel lectin with antiproliferative and HIV-1 reverse transcriptase inhibitory activities from dried fruiting bodies of the monkey head mushroom Hericium erinaceum[END_REF].

The nutritional values and important medicinal properties of H. erinaceus are well-known in Asia, Europe, and North America. H. erinaceus normally requires temperatures of 22°C to 25°C for optimal mycelial growth and 18°C to 24°C to produce fruiting bodies. The mycelium of H. erinaceus from artificial media and fruiting body from artificial cultivation are illustrated in Fig. 12. The first publication on the cultivation of this mushroom on artificial logs and polypropylene bags was documented in 1988 [START_REF] Suzuki | Cultivation of Yamabushitake (Hericium erinaceum)[END_REF]. However, the cultivation conditions did not affect selected bioactive properties of this mushroom grown in tropical Malaysia (Wong et al. 2009b;[START_REF] Abdulla | Effect of culinary medicinal lion's mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) on ethanol induced gastric ulcers in rats[END_REF][START_REF] Abdulla | Potential activity of aqueous extract of culinary medicinal Lion's Mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (Aphyllophoromycetideae) in accelerating wound healing in rats[END_REF]. The comparison of chemical components and biological activity of H. erinaceus fruiting body and mycelial extracts have been evaluated. The polysaccharide content of fruiting body extracts with protective effect on the gastric mucosa was 7.92% higher than that of mycelial extracts, while monosaccharide and protein contents were similar [START_REF] Yang | Hypolipiddemic effect of an exo-biopolymer produced from a submerged mycelial culture of Hericium erinaceus[END_REF].

Therefore, medicinal properties from cultures and fruiting bodies may also provide different and undiscovered therapeutic benefits.

Many promising novel drugs and commercial products in variable forms of H. erinaceus have served as remarkable finds in the history of disease treatments, especially immunosuppressive agents.

Sandwich biscuits with the fruiting bodies of H. erinaceus were used in the prevention and therapeutic treatment for nutritional anemia of preschool children [START_REF] Liu | A study on preparation of sandwich biscuits with hedgehog fungus and therapeutic approach for nutritional anemia of preschool children[END_REF]. The extract of dried fruiting bodies and mycelial culture were prepared for healthy beverages such as a sport drink (11 th Asian Sport Festival in China, 1990) and tea that can be used for improving liver function and preventing diabetes in China [START_REF] Imtiaj | Vegetative growth of four strains of Hericium erinaceus collected from different habitats[END_REF][START_REF] Qin | Medicinal mushroom for prevention of disease of modern civilization[END_REF][START_REF] Wang | Hypoglycemic effect of extract of Hericium erinaceus[END_REF]). In the hospitals of China, tablets of H. erinaceus were found to be an effective treatment of anti-aging, inflammation, chronic gastric, esophageal carcinoma, and digestive tract ulcer and their use extended the life of cancer patients [START_REF] Chen | Studies on the cultivation and medicinal efficacy of Hericium erinaceus, the edible fungus. The Edible Fungus Research Institute of the Shanghai Academy of Agricultural Science[END_REF]Li et al 2014a;[START_REF] Liu | A study on preparation of sandwich biscuits with hedgehog fungus and therapeutic approach for nutritional anemia of preschool children[END_REF][START_REF] Poucheret | Biological and pharmacological activity of higher fungi[END_REF][START_REF] Ying | Icones of medicinal fungi from China (translated, Yuehan X)[END_REF]. Capsule supplements of 100% pure powder of H. erinaceus are marketed in Malaysia to promote regeneration after peripheral nerve injury [START_REF] Wong | Gastroprotective effects of lion's mane mushroom Hericium erinaceus (Bull.:Fr.) Pers. (Aphyllophoromycetideae) extract against ethanol-induced ulcer in rats[END_REF]. Such effects reflect that H. erinaceus can be a good candidate for promoting health through combination with extracts of other herbal and medicinal mushrooms, which can be made available in variable forms, such as beverages, powder, capsules, or pills [START_REF] Lakhanpal | Medicinal and nutraceutical genetic resources of mushrooms[END_REF][START_REF] Smith | Medicinal mushrooms: a rapidly developing area of biotechnology for cancer therapy and other bioactivities[END_REF][START_REF] Wong | Neuroregenerative potential of lion's mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (higher basidiomycetes), in the treatment of peripheral nerve injury:-Review[END_REF][START_REF] Zhuang | Anti-dementia substance from Hericium erinaceum and method of extraction[END_REF]). An interesting future application for glucanes from medicinal mushrooms may be their use in pharmaceuticaltechnology. Polysaccharides derived from H. erinaceus were used to encapsulate curcumin nanoparticles for use in antitumor drug delivery, employing nanoprecipitation techniques [START_REF] Huong | Preparation and antitumor-promoting activity of curcumin encapsulated by 1,3-β-glucan isolated from Vietnam medicinal mushroom Hericium erinaceum[END_REF].

Moreover, exciting recent research has claimed biological activities of these compounds at the level of clinical trials. Thus, H. erinaceus is now being used as food supplement and medicinal nutrition therapy with enhancement of the immune function of the whole human body. However the therapeutic potential and development of pharmaceutical standards for extraction of compounds from the fruiting bodies and even standardisation of producton through mycelial cultures (e.g. by GMP facilities) still constitutes a future challenge.

Available commercial products from H. erinaceus that provided beneficial effects in prevention of various diseases, and supplementary foods that improve health showed no side effects are shown in Table 6. These products are mostly being sold over the counter (some are distributed via the Internet) and do not constitutedrugs, but rather can be categorised as nutraceuticals. This also means that their production does not necessarily meet the standards of pharmaceutical drugs.

Nevertheless, H. erinaceus has been on the list of 'Nature's Nutrient for the Neurons' which refers to its potential to stimulate nerve growth factor synthesis [START_REF] Kawagishi | The anti-dementia effect of Lion's Mane mushroom and its clinical application[END_REF]). Recent inventions relating to hericenones and erinacines as medicine through nutraceutical products or medicinal products for patients suffereing from neurological diseases have been claimed in patent applications.

Pharmaceutical compositions containing erinacerins A and B have been recently claimed in patents as excellent brain protective agents for preventing dementia disease (Fan 2014; Kim et al. 2014;Noh et al. 2014). Promising innovations in nutraceuticals as well as pharmaceuticals refer to stimulators of nerve growth factor by erinacines, which can only be isolated from cultured mycelia is still extremely interesting because of better outcomes.

Conclusion

H. erinaceus is distinguished as an edible-medicinal mushroom and also a delicacy for food supplement and has earned much attention as a potential source of various pharmaceutical properties.

It has been used for more than 1000 years in China and for many decades in other oriental countries [START_REF] Mizuno | Bioactive substances in Hericium erinaceus (Bull.: Fr.) Pers. and its medicinal utilization[END_REF][START_REF] Jia | Structural investigation of a novel rhamnoglucogalactan isolated from the fruiting bodies of the fungus Hericium erinaceus[END_REF][START_REF] Ying | Icones of medicinal fungi from China (translated, Yuehan X)[END_REF]. Pharmacological effects of H. erinaceus have been examined over the last 20 years. Polysaccharides isolated from fruiting bodies of H. erinaceus have shown significant suppression of various tumor cells in both in vitro and in vivo based experiments (Lee & Hong, 2010a;[START_REF] Mizuno | Antitumor-active polysaccharides isolated from the fruiting body of Hericium erinaceum, an edible and medicinal mushroom called Yamabushitake or Houtou[END_REF]Wang et al. 2001a). Mycelial cultures of H. erinaceus are used to extract bioactive compounds and are processed in tablets, and are now produced in large scale, mainly for curing gastric ulcer and chronic gastricism and esophagus cancers [START_REF] Xu | A doubleblind study of effectiveness of Hericium erinaceus Pers. therapy on chronic atrophic gastritis. A preliminary report[END_REF]Li et al. 2014). Extracts containing erinacines from mycelium and hericenones from fruiting bodies have provided evidence that H. erinaceus can stimulation nerve growth factors (NGF).

Studies have identified the effectiveness of bioactive compounds from H. erinaceus that may be able to pass through the brain-blood barrier into the brain to stimulate NGF synthesis, while harmful effects have not been reported. Worldwide clinical trial data have verified beneficial properties of this mushroom and provided dietary supplements of high market value. Several bioactive compounds thought to be excellent therapeutic agents offer solutions for future drug discovery. However, uncharacterized polysaccharides must still be determined for their potential health benefits. Additionally, the potential pathways and mechanisms that different compounds affect to stimulate human immune responses still remain to be elucidated.

List of Figure legends

Synonyms

Clavaria erinaceus (Bull.) Paulet.

Dryodon erinaceus (Bull.) P. Karst.

Clavaria conferta Paulet

Dryodon caput-medusae (Bull.) Quél.

Dryodon juranus Quél.

Hericium caput-medusae (Bull.) Pers.

Hericium echinus (Scop.) Pers. Merisma hystrix (Pers.) Spreng.

Hericium grande

Steccherinum quercinum Gray

Fig. 1

 1 Fig.1

Fig. 2

 2 Fig. 2 Chemical structures of erinacerins and erinapyrones

  Raf.Hericium hystrix Pers.Hericium unguiculatum (Pers.) Legon and A. Henrici Hydnum caput-medusae Bull., Hydnum echinus (Scop.) Fr.Hydnum erinaceus Bull.Hydnum grande (Raf.) Steud.Hydnum hystricinum Batsch,Hydnum hystrix (Pers.) Fr.Hydnum juranum (Quél.) Sacc. and D. Sacc.Hydnum omasum PanizziHydnum unguiculatum (Pers.) StreinzManina cordiformis Scop.Martella echinus Scop.Martella hystricinum (Batsch) KuntzeMartella hystrix (Pers.) Lloyd Merisma caput-medusae (Bull.) Spreng.

Fig. 1

 1 Fig. 1 Fruiting bodies of H. erinaceus; a. mature fruiting body on deadwood; b. mature fruiting body

Fig. 12 Fig

 12 Fig. 12 a. Mycelium of H. erinaceus from artificial media; b. fruiting body from artificial culture.

  Fig.3

Table 1

 1 Overview of taxonomic synonyms for Hericium erinaceus. For details see Index Fungorum (http://www.indexfungorum.org/) and Mycobank (http://www.mycobank.org/)

	Hericium erinaceus (Bull.) Pers. 1797

Varieties and formae (all currently regarded assynonyms)

  Hericium erinaceus f. caput-medusae (Bull.) Nikol.Hericium erinaceus subsp. erinaceo-abietis Burds., O.K. Mill. and Nishij.Hericium erinaceus subsp. unguiculatum Pers.Hericium erinaceus var. sulphureum Pers.Hericium erinaceus var. viridescens Pers.

Table 2

 2 Overview of some species accepted in the genus Hericium and their distribution

	Name	Basidiome morphology	Basidiospores size/	Host	Locality
			characteristics
	Hericium abietis (Weir ex	Compact branched structure	4.5-5.5×4-4.5 μm	coniferous wood	Northwest
	Hubert) K.A. Harrison	from which long spines			America
		hanging down of teeth with
		cream white shades
	Hericium alpestre Pers.	Branches, hymenophore	5-6.5 x 4.5-5.5 µm,	Abies alba	Europe
		hydnoid, with branched spines
		up to 2 cm long with cream
		shades
	Hericium americanum Ginns	Branches stout and branching	5-7 x 4.5-6 µm	Fagus, Acer, Carya	North
		repeatedly, white, becoming		and Quercus	America
		cream-colored in age
	Hericium bharengense	Hymenophoral , sterile and	4.9×4.0 µm, low	Tsuga dumosa	Sikkim,
	K. Das, Stalpers and U. Eberh.	fertile branching pattern,	ornamentation (0.2 μm high)		India
		presence of moderately long
		spines, white shades
	Hericium cirrhatum Nikol.	Pileate basidiomes	inamyloid	dead wood of Fagus Europe
		Spines are pointed and usually	3.5-4.5 x 3-3.5µm
		little more than 1 to 1.5cm
		long, with little or no real stem
		with cream shades

Table 3

 3 Bioactive compounds from the fruiting bodies of H. erinaceus. Why the 3 first molecules are not drawn ?

	Bioactive compound	Biological activity

Acknowledgments

We are grateful to Samantha Chandranath Karunarathna and Komsit Wisitrassameewong (Mae Fah Luang University) for their help and discussions. Our warmest thanks go to Bettina Haberl, Eduard Löwen, Harry Andersson, Peter Karasch and Vivien Bedregal for providing excellent photographs. This study was financially supported by Thai Royal Golden Ph.D. Jubilee-Industry (RGJ) program (Ph.D/0138/2553 in 24.S.MF/53/A.3) and German Academic Exchange Service (DAAD) and joint TRF-DAAD PPP (2013-2014). K.D.Hyde would like to thank the Thailand Research Fund for a grant on taxonomy, phylogeny and biochemistry of Thai Basidiomycetes (BRG 5580009).

Funding Information: Thai Royal Golden Ph.D. Jubilee-Industry (RGJ) program ((Ph.D/0138/2553 in 24.S.MF/53/A.3)) Miss Benjarong Thongbai Thailand Research Fund (TH) (BRG 5580009)

Target organ Source of extracts Test References

Breast carcinoma (MCF-7)

Fruiting bodies in vitro [START_REF] Zhuang | Anti-dementia substance from Hericium erinaceum and method of extraction[END_REF], 2010[START_REF] Li | A novel lectin with antiproliferative and HIV-1 reverse transcriptase inhibitory activities from dried fruiting bodies of the monkey head mushroom Hericium erinaceum[END_REF] Cervical carcinoma Fruiting body in vitro Kawagishi et al. 1990aKawagishi et al. , 1990b Colon carcinoma (CT-