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; Thawthong et al. 2014; Wasser 2011; Wisitrassameewong et al. 2012). Several classes of mushroom metabolites have been classified as effective immunity-boosting molecules, including proteins, polysaccharides, lipopolysaccharides, and glycoproteins (Wang et al. 2001b; Keong et al. 2007). Mushrooms also produce and accumulate several low-molecular weight secondary metabolites, including phenols, polyketides, and terpenes, that are effective medications (Wong et al. 2007; De Silva et al. 2013). For example, it has been found that mushroom phenolic compounds are outstanding antioxidants that lack mutagenic properties (Khatua et al. 2013). 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 (Donatini 2011; Richter et al. 2015). 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 (Ramberg et al. 2010). Scientists have also screened the antimicrobial properties of mushrooms to find a solution for antibiotic drug resistance in human pathogenic microorganisms (Anke et al. 1977; Lindequist et al. 2005; Suay et al. 2000).

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 (Kirk et al. 2008). 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.

Table 1 Overview of taxonomic synonyms for Hericium erinaceus
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Etymology and trivial names: erinaceus literally means “hedgehog” in Latin. The name was proposed by Bulliard, 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 “mountain priest”. In China, the mushroom goes by the name “猴頭菇” (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, which 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 (Ginns 1985; Harrison 1973). 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; Maas Geesteranus 1971; Koski-Kotiranta and Niemelä 1987). Confusion stems from the fact that the long-spined species of Hericium may have short spines (1 cm in length or less) 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 (Harrison 1973; Koski-Kotiranta and Niemelä 1987; Stamets 2005).

Notably, H. erinaceus has a long history of use in traditional Chinese medicine (TCM) 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 the Global Biodiversity Information Facility (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. Hallenberg et al. 2012; Zhou and Dai 2013).

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 (Boddy and Wald 2003, 2004, 2011; Boddy et al. 2004, 2011). 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 (Govaerts et al. 2011).

The fungus can also easily be discriminated from its closest relatives by molecular methods. A set of polymerase chain reaction (PCR) primers specific to the internal transcribed spacer (ITS) nrDNA locus of Hericium species has been developed successfully, which can be used to quickly identify H. erinaceus (Lu et al. 2002; Parfitt et al. 2005). 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 new to science with phylogenetic inference, viz. H. bharengense and H. yumthangense from Himalaya, India (Das et al. 2011, 2013) and H. rajchenbergii from Argentina (Hallenberg et al. 2012). Table 2 gives an overview of species in the genus Hericium that were published from the 19 – 20th century. Basidiomes of H. erinaceus in the natural habitat are shown in Figs. 1a and b.

Table 2 Overview of some species accepted in the genus Hericium and their distribution
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Fig. 1
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Fruiting bodies of H. erinaceus; a mature fruiting body on deadwood, b mature fruiting body on heartwood of living trees. Photos taken by Bettina Haberl (a) and Vivien Bedregal (b), in Germany

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Chemical composition of fruiting bodies vs. cultured mycelia

Numerous types of biologically active compounds from mushrooms have been demonstrated pharmaceutical activities and therapeutic properties. In particular, their bioactive polysaccharides have been extensively studied for potential and existing applications in pharmaceuticals and functional foods (Giavasis 2014; Mizuno and Nishitani 2013). 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. Cui et al. (2010), Hu et al. (2008), Kulisic et al. (2004), Lee et al. (2010b), Malinowska et al. (2009) 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. Li et al. (2015) 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 weight 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 (Shen et al. 2010). 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 basidiomes. 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 two-dimensional nuclear magnetic resonance (2D-NMR) for the detection and identification of bioactive secondary metabolites have been developed (Bills and Stadler 2014). However, Shen et al. (2014) 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 (Kawagishi et al. 1994; Shen et al. 2010; Mizuno et al. 1992). We will first 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 Dong et al. 2006 and 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 (Mizuno et al. 1992). 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. Jia et al. (2004) isolated a heteropolysaccharide with molecular weight of 1.8 × 104 Da, which is composed of monosaccharides, including rhamnose, galactose, and glucose. Zhang et al. (2006, 2007) found a hetero-polysaccharide with a molecular weight of 1.9 × 104 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 D-glucopyranosyl residues with single galactose branches (Dong et al. 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 weight secondary metabolites have recently been isolated from mycelial cultures and fruiting bodies of H. erinaceus. In general, these metabolites have 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 significant biological activities are known (Yaoita et al. 2005; Fig. 2). Several chlorinated aromatic compounds are also known from submerged cultures of the mushroom (Ueda et al. 2009). These metabolites are well-known to exhibit non-specific 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 pyranones were also isolated from submerged cultures (Qian et al. 1990; Kawagishi et al. 1992;) and two of them, erinapyrone A (4) and B (5) (Fig. 2), showed cytotoxicity against HeLa S3 cells (Kawagishi et al. 1992; Mizuno 1999). 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, 3, 4, 5, 6, 7, 8, 9, 10 and 11. Many of these compounds are treated below in the chapters about various bioactivities of Hericium.

Fig. 2
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Chemical structures of erinacerins and erinapyrones

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Table 3 Bioactive compounds from the cultured mycelia of H. erinaceus.
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Fig. 3
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Chemical structures of selected cyathane diterpenoids from submerged cultures of H. erinaceus

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Fig. 4
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Chemical structures of chlorinated aromatic compounds, benzopyrans, benzofurans and an ergosterol derivative isolated from Hericium erinaceus

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Fig. 5
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Chemical structures of two metabolites from H. erinaceus with anti-tumor and immune-modulating activities

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Fig. 6
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Chemical structures of metabolites from Hericium with anti-hyperglycemic and anti-hypocholesterolemic activities

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Fig. 7
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Chemical structures of selected hericenone derivatives

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Fig. 8
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Chemical structures of erinacines and other cyathane diterpenes with neuroprotective effects from H. erinaceus (Part 1)

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Fig. 9
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Chemical structures of erinacines and other cyathane diterpenes with neuroprotective effects from H. erinaceus (Part 1I)

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Fig. 10
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Chemical structures of miscellaneous metabolites of H. erinaceus with antimicrobial activities

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Fig. 11
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Chemical structures of miscellaneous metabolites of H. erinaceus with phytotoxic activities

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Hericium erinaceus was selected as a biotransformation model species, as it is well-known for efficient terpenoid production 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) (Kenmoku et al. 2001; Fig. 3). Erinacine E has an unique structural feature as compared with other cyathane diterpenoids and was converted to CP-412,065 (7) (Saito et al. 1998; Fig. 3) by using Caldariomyces fumago. Detailed studies on the biosynthesis of erinacine-like metabolites were already conducted by Anke et al. (2002) based on herical (later also reported as erinacine P (42)); a derivative of this type that was first found in “H. ramosum” (current name H. coralloides).

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 (Huh et al. 2003). An ethanol extract from H. erinaceus cultivated on Artemisia capillaries inhibited gastric mucosal damage in rats in a dose-dependent-manner with an effective dose 50 (ED50) value of 22.6 mg/kg (Choi et al. 2012). In addition, the same extract significantly attenuated hepatic lipid deposits and reduced oxidative stress in the liver of male Sprague–Dawley rats (Choi et al. 2011). 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 (Lee et al. 2003; Choi et al. 2005). 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 (Du et al. 2013; Wang et al. 2014). Recently, a novel fibrinolytic metalloprotease named herinase with a molecular mass of 51 kDa was identified from the fruiting bodies (Choi et al. 2013). 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 from mushrooms 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; Hiwatashi et al. 2010; Wasser 2002; Yang et al. 2003). Hericium erinaceus has been a traditional mushroom in Eastern Asia since ancient times for treating neurasthenia and general debility (Ying et al. 1987). 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 (NO). 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 doxorubicin-mediated apoptotic signaling via suppression of nuclear factor kappa B (NF-κB) activity (Lee et al. 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. Han et al. (2009) and Lee and Hong (2010) found that polysaccharides from aqueous extracts had anti-hepatocarcinoma activity and activated natural killer (NK) cells indirectly through induction of IL-12 in splenocytes (Yim et al. 2007; Xu et al. 1994). ß-glucans extracted from submerged a mycelial culture of H. erinaceus showed significant anticancer properties in animal systems. Liu et al. (2000) 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 intra-cutaneously transplanted on their backs was demonstrated by Kim et al. (2011c, 2013). 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 NK cells. 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 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).

Table 4 Anti-tumor activities of H. erinaceus demonstrated in vivo and in vitro.
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Additionally, there 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 (18) showed significant anti-tumor 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-κB 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 (Lai et al. 2013). 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 (Park et al. 2008). 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, fat and cholesterol (Lau et al. 2012; Phillips et al. 2011; Thawthong et al. 2014; Ulziijargal and Mau 2011). 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 (Ali et al. 2012). 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 (Hikino et al. 1989; Sato et al. 2002; Teng et al. 2012; Badole et al. 2006). The potential anti-hyperglycemia effect of extracts from fruiting bodies and mycelia of H. erinaceus has also been reported in diabetic animals. Vertesy et al. (1999) tested the phthalaldehyde derivatives, hericenals A (19), B (20) and C (21) 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 (Yang et al. 2003; 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 anti-hyperglycemic effects in diabetic rats (Wang et al. 2005; Hiwatashi et al. 2010). These components also showed significant anti-hypercholesterolemic effects and reduced the plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, phospholipid, atherogenic index and hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity. Rats given an oral administration of extract of H. erinaceus had increased plasma high-density lipoprotein cholesterol (HDL-C) levels as compared to the control group fed with saline (Yang et al. 2002; Yang et al. 2003; Wang et al. 2005).

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 (Wang et al. 2005; Liang et al. 2013). Significantly lower elevation rates of blood glucose level and increased serum insulin level occurred in rats fed with a methanol extract of H. erinaceus (HEM), as compared with untreated control groups. In another study, the mycelial ethanol extract of the mushrooms significantly reduced serum content of LDL-C by 45.5 % and effectively increased HDL-C by 31.1 % in serum of diabetic mice (Yang et al. 2003). 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 (Hiwatashi et al. 2010). 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 (Choi et al. 2005). 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 (Obara and Nakahata 2002). 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 NGF on neuronal cells and on several non-neuronal cells and explained the possible mechanism of NGF on cells of the immune system (Levi-Montalcini et al. 1996; Aloe 2004).

It is assumed that functional deficiency of NGF is related to Alzheimer’s disease (AD) and is expected to be applied to the treatment of Alzheimer’s disease patients (Allen and Dawbarn 2006). 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 (Shen 2004; Prine et al. 2014). AD is identified in patients by synaptic injury deficiency of neurotransmitters, un-functioning and/or death of neural cells, and possibly by interference with the process of adult neurogenesis in the hippocampus (Crews and Masliah 2010). AD patients have abnormal accumulation of amyloid-ß peptide containing neurofibrillary tangles composed of hyperphosphorylated tau proteins (Murphy and Harry 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 five million Americans live with AD and this number will increase by an average of 50 % by the year 2025 (Anonymous 2008; Gaugler et al. 2014; Prince et al. 2014). However, the efficacy of current drugs for the treatment of AD patients is still unclear.

The endoplasmic reticulum (ER) is one of the important organelles triggering a specific program of cell death via induced apoptotic pathways with a signaling between the ER and mitochondria and , therefore, also constitutes a valid target for neuroprotective drugs (Ueda et al. 2008). ER stress causes brain cells to die, which leads to development of neurodegenerative diseases. Dilinoleoyl-phosphatidylethanolamine (DLPE) isolated from H. erinaceus appears to reduce ER stress and amyloid-β peptide (A-β ) toxicity by decreasing neuronal cell death of neuro-2a cells via the protein kinase C pathway (Nagai et al. 2006). Another strongly bioactive compound named 3-hydroxyhericenone F (28), showed protective activity against neuronal cell death of neuro-2a caused by ER stress (Ueda et al. 2008). Furthermore, the functional independence measure (FIM) score regarding disease progression of preliminary clinical trials showed improvement in patients with dementia (Kawagishi and Zhuang 2008).

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 (Kolotushkina et al. 2003). Organic extracts from fruiting bodies of H. erinaceus demonstrated neurotrophic effects enhancing the myelination process in the mature myelinating fibers in vitro assays (Moldavan et al. 2007). Mori et al. (2008) reported that ethanol extracts of H. erinaceus can stimulate NGF 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. Mori et al. (2009) found significant prevention of cognitive impairment with H. erinaceus powder from air-dried fruit bodies. A double-blind, parallel-group, placebo-controlled clinical study was performed with oral administration of H. erinaceus on 50–80 years 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 Institute for Cancer Research (ICR) mice induced by amyloid-β peptide (Mori et al. 2009). Oral administrations of the aqueous extract from fruiting bodies of H. erinaceus promoted regeneration of an injured adult female Sprague–Dawley rat nerve-injury during the early stage of recovery (Wong et al. 2009a; Wong et al. 2011).

NGF is easily metabolized by peptidases and is also unable to cross the blood–brain 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 NGF biosynthesis. Hericenones and erinacines are low-molecular weight compounds that can easily cross the blood–brain barrier (Moldavan et al. 2007; Kawagishi and Zhuang 2008; Shin 2011). However, the detailed mechanism by which erinacines and hericenones induces NGF 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 an increase of 60.6 % on neurite outgrowth stimulation and induced NGF synthesis in neuroblastoma-glioma cell line NG108-15 (Kenmoku et al. 2001; Lai et al. 2013).

Hericenones A (22) and B (23) were originally isolated from the fruiting bodies of H. erinaceus and showed significant cytotoxicity against HeLa cells (Kawagishi et al. 1990a). However, Hericenones C (24), D (25), E (26) and H (30) exhibited stimulating activity in the synthesis of NGF in vitro. The hericenones F (27) and G did not stimulate NGF synthesis under the same conditions (Kawagishi et al. 1991, 1993; Mizuno 1999). Furthermore, hericenones I (31), J (32) and L were also identified, and hericenone L showed cytotoxic activity against EC109 tumor cells (Ma et al. 2012; Fig. 7). There is a debate as to whether hericenones are active components stimulating biosynthesis of NGF. Other studies have reported that hericenones C and D do not increase NGF biosynthesis in cell line 1321N1 (Mori et al. 2008). Hericenone E was able to stimulate NGF synthesis in rat pheochromocytoma (PC12) cells when investigated using several pharmacological inhibitors. Hericenone E was able to stimulate NGF 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 signal-regulated kinases (MEK/ERKs) pathway and also increased protein kinase B (PKB; Phan et al. 2014).

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 NGF synthesis have already been found. Erinacines A (33), B (34), C (35), D (36), E (37) F (38), G (39), H (40), and I (41) showed a stronger biological activity that stimulates NGF synthesis than epinephrine used as a positive control on murine astroglial cells (Kawagishi et al. 1994, 1996a, b; Lee et al. 2000; 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 NGF in the rat’s locus caeruleus and hippocampus, but not in the cerebral cortex in an oral administration study (Shimbo et al. 2005). A cyathane-xyloside, erinacine P (42) and its biomimetic conversions into erinacine A and erinacine B was also found to induce NGF syntheses compared with epinephrine as a positive control (Kenmoku et al. 2000; Fig. 9).

Kenmoku et al. (2002) isolated erinacine Q (43) and reported its biosynthetic route to erinacine C. A cyatha-3,12-dien-14-β-ol named erinacol (44) and 11-O-acetylcyathin A3 (45), both of which are probably biosynthetically related to erinacine Q, were isolated by Kenmoku et al. (2004) and also reported to have NGF-enhancing activities. The stereochemistry of erinacine R (46) 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 (Hazekawa et al. 2010; Mori et al. 2008, 2009, 2011; Phan et al. 2014). Lee et al. (2014) 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 NGF synthesis. However, further studies need to determine the mechanism of hericenones and erinacines, whether the compounds are able to stimulate NGF 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.

Table 5 Pharmacological effect of extracts from H. erinaceus demonstrated in human double blind clinical trials
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d) Antimicrobial activity

Medicinal mushrooms are rich sources of secondary metabolites with activity against a wide range of microorganisms including bacteria, yeasts and filamentous fungi. These substances include diterpenoids, such as pleuromutilin from the genus Clitopilus, which led to the discovery of the marketed drug retapamulin (Kilaru et al. 2009). Other antibiotics have been isolated from Ganoderma (Richter et al. 2015) and many other species. It is hoped that further research on antimicrobial agents from basidiomycetes will lead to alternative antibiotic drugs on the market (De Silva et al. 2013; Stadler and Hoffmeister 2015). 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 (14), 4-chloro-3,5-dimethoxylbenzaldehyde (15) and chlorinated orcinol from mycelial extracts possessed antimicrobial activity (Okamoto et al. 1993). The submerged cultures contained hericene A (47), B (48), C (49) and erinapyrone C (6), which showed moderate bioactivities against gram-positive bacteria (Alberto et al. 1995; Kawagishi et al. 1992; 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 (Lindequist et al. 2005; 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 an EC50value of 5.5 μl/ml against Staphyloccocus aureus (Kim et al. 2000). Furthermore, cyathane derivatives named erinacines J (50) and K (51) were tested for their effectiveness against MRSA. Only erinacine K showed anti-MRSA activity in the direct drop and MIC bioassays. This was attributed to chemical substitutions present in the three-ring skeleton of the aglycon in biologically active compounds expressing anti-MRSA activity (Kawagishi 2005; Kawagishi et al. 2006; Fig. 10). In clinical tests conducted by a Japanese group, MRSA was reported to have disappeared in a percentage of patients whose diet was supplemented with extracts of both fruiting body and mycelium of H. erinaceus (Kawagishi 2005).

More recently, Kim et al. (2012a) found 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 (Shang et al. 2013). 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) can cause oxidative stress which leads to a variety of diseases, including cancer, AD, cardiovascular disease, and the aging process (Ames et al. 1993; Halliwell 2012). This mechanism can produce free radicals or various ROSs 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 (Krishnaiah et al. 2010; Valko et al. 2007).

Many studies have been carried out to investigate antioxidant properties of H. erinaceus (Abdullah et al. 2012; Fu et al. 2002; Malinowska et al. 2009; Mau et al. 2002; Mujić et al. 2011). An investigation of phenolics from mycelium extracts in hot water of H. erinaceus has been reported to evaluate the in vitro antioxidant activities by Abdullah et al. (2012; Ferreira et al. 2009).

Another study reported on the antioxidant properties of phenolic compounds from fruiting bodies and mycelia. Mycelial extracts showed 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 (LPSs) from mycelia showed significant anti-oxidative activities in BALB/C mice through the elevation of hepatic glutathione levels (Jang et al. 2010). Han et al. (2013) 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 enzyme 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 in vitro assays. These results suggested that H. erinaceus extracts can be a good source for increasing antioxidant enzyme activities in humans. Xu et al. (2010) also found that β-glucanes from H. erinaceus showed significant anti-skin aging properties, due to inhibition of matrix metalloproteinase (MMP)-1, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 activities in aged rat models. These data, however, have, so far, not been 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 a 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 (Abdulla et al. 2008). 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 (Abdulla et al. 2011). 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 (Abdulla et al. 2008; Wong et al. 2013).

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 and suffered from severe acute respiratory failure with diffuse infiltration in both lungs. The lymphocyte stimulation test showed a strong reactivity against H. erinaceus extract administered daily for four months (Nakatsugawa et al. 2003). 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 the fruiting body also exerts anti-platelet action. Hericenone B showed stimulating activity on release arachidonic acid, which mediated receptor thrombosis via collagen through α2/β1 in a 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 of aspirin as a reference investigated in vivo (Farndale et al. 2004; Mori et al. 2010).

Hericium erinaceus also contains a biologically active substances that showed activities on plant-growth. Hericerin (52), for instance, showed activity against pine pollen germination and tea pollen growth (Kimura et al. 1991; Kobayashi et al. 2012; Fig. 11). The recently-isolated erinaceolactones A (53), B (54) and C (55) isolated from mycelial cultures exhibited plant-growth regulatory activity (Wu et al. 2015; Fig. 11).

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. Hyde et al. (2010) 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 novel kinds 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 USA, 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 (Anand et al. 2008; Dicken et al.2005). It 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 (Li et al. 2010).

The nutritional value and important medicinal properties of H. erinaceus are well-known in Asia, Europe, and North America. H. erinaceus normally requires temperatures of 22–25 °C for optimal mycelial growth and 18–24 °C to produce fruiting bodies. The mycelium of H. erinaceus from artificial media and fruiting bodies 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 (Suzuki and Mizuno 1997). However, the cultivation conditions did not affect selected bioactive properties of this mushroom grown in tropical Malaysia (Wong et al. 2009b; Abdulla et al. 2008; Abdulla et al. 2011). 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 (Yang et al. 2003). Therefore, medicinal properties from cultures and fruiting bodies may also provide different and undiscovered therapeutic benefits.

Fig. 12
figure 12

a Mycelium of H. erinaceus from artificial media, b fruiting body from artificial culture. Photos taken by Eduard Löwen and Peter Karasch, respectively in Germany, 2013

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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 (Liu et al. 1992). The extract of dried fruiting bodies and mycelial culture were prepared for healthy beverages such as a sport drink (11th Asian Sport Festival in China, 1990) and tea that can be used for improving liver function and preventing diabetes in China (Imtiaj et al. 2008; Qin et al. 2015; Wang et al. 2005). 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 (Chen 1992; Li et al. 2014a; Liu et al. 1992; Poucheret et al. 2006; Ying et al. 1987). Capsule supplements of 100-% pure powder of H. erinaceus are marketed in Malaysia to promote regeneration after peripheral nerve injury (Wong et al. 2013). 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 (Lakhanpal and Rana 2005; Smith et al. 2002; Wong et al. 2012; Zhuang et al. 2009). An interesting future application for glucanes from medicinal mushrooms may be their use in pharmaceutical technology. Polysaccharides derived from H. erinaceus were used to encapsulate curcumin nanoparticles for use in antitumor drug delivery, employing nanoprecipitation techniques (Huong et al. 2011).

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 a food supplement and in 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 production through mycelial cultures [e.g., by 'good manufacturing practice' (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 without 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 constitute drugs, 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 NGF synthesis (Kawagishi et al. 2004). Recent inventions relating to hericenones and erinacines as medicine through nutraceutical products or medicinal products for patients suffering from neurological diseases have been claimed in patent applications. Pharmaceutical compositions containing erinacerins A and B have been recently claimed as excellent brain protective agents for preventing dementia disease (Kim et al. 2014; Noh et al. 2014). Promising innovations in nutraceuticals as well as pharmaceuticals refer to stimulation of NGF by erinacines, which can only be isolated from cultured mycelia. This research is still extremely interesting because of potential better outcomes.

Table 6 Examples of patented products of mushroom extracts with claimed biological and pharmacological properties
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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 (Vertesy et al. 1999; Jia et al. 2004; Ying et al. 1987). The 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 experiments (Lee et al. 2010a; Mizuno et al. 1992; 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 ulcers and chronic gastricism and esophageal cancers (Xu et al. 1994; Li et al. 2014a, b, c). Extracts containing erinacines from mycelium and hericenones from fruiting bodies have provided evidence that H. erinaceus can stimulate 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.