Introduction
Hericium is an edible, wood rotting fungus of temperate deciduous forests (Grace & Mudge, 2015). It is a culinary-medicinal mushroom and has a long history of usage in traditional Chinese medicine as a tonic for stomach disorders, ulcers and gastrointestinal ailments (Xu et al., 1985). Recently it has received increased attention for its potential therapeutic and neuroprotective capabilities (Spelman et al., 2017). Several scientific studies have documented the medicinal or health beneficial effects of fruit bodies and mycelium of Hericium mushrooms and their chemical extracts.
Most studies have been conducted for Hericium erinaceus (HE), but studies examining Hericium coralloides (HC) and Hericium americanum (HA) can also be found (Atila, 2019). HE (see Figure 1) is also called yamabushitake, houtou, bearded hedgehog mushroom, lion’s mane mushroom, or bearded tooth fungus in Japan, China, the USA and various other countries. The aim of this article is to gather available information about health-promoting benefits and medicinal properties of Hericium mushrooms with a focus on HE.
In Europe, Hericium is rare in natural habitats but can be successfully cultivated. In contrast, it is common in Japan and North America and its artificial cultivation has been developed in large quantities in Asia. Both fruitbodies and mycelia are rich in bioactive, health promoting substances, including β-glucan polysaccharides, hericerins, hericenones and erinacine, resorcinols, terpenoids, isoindolinones and sterols. In general, the bioactive metabolites from Hericium 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; Ma et al., 2010; Mizuno & Nishitani, 2013).
The reported health-promoting properties of the mushroom fruit bodies, mycelia, and purified bioactive compounds include antibiotic, anticarcinogenic, antidiabetic, antifatigue, antihypertensive, antihyperlipidemic, antisenescence, cardioprotective, hepatoprotective, nephroprotective, and neuroprotective properties and improvement of anxiety, cognitive function, and depression. The described anti-inflammatory, antioxidative, and immunostimulating properties in cells, animals, and humans seem to be responsible for these multiple health-promoting properties (Friedman, 2015).
Toxicological studies
Consumption of Hericium mushrooms is relatively safe for human consumption and most of the medicinal properties of Hericium extracts from fruiting bodies and mycilia have been studied in animal models for nearly three decades. Moreover, the different bioactive metabolites derived from HE are supposed to be safe when used as pharmaceutical products and dietary supplements, as less side effects are excpected from compounds of natural origin compared to synthetic compounds.
In a sub-chronic toxicity study in rats with an oral administration of aqueous extracts of HE at doses of up to 1000 mg/kg body weight for 90 days, no mortality or morbidity was observed in all the treated and control rats (Lakshmanan et al., 2016). Moreover, no adverse effect on the general behaviour, body weight, haematology, clinical biochemistry, and relative organ weights was observed. In another animal study, the acute oral LD50 of HE mycelia enriched with its active compounds was found to be higher than 5 g/kg in rats (Li, Chen, et al., 2018), indicating that the mycelium is reasonably safe in cases of overdose. Repeated daily doses of HE mycelium enriched with its active compounds up to 3 g/kg has also been used without any adverse effects in rats (Li, Chen, Lee, et al., 2014). Moreover, HE mycelium was found not to be mutagenic in the bacterial reverse mutation test, in vitro chromosome aberration test, and in vivo erythrocyte micronucleus test, with and without metabolic activation (Li, Chen, Chen, et al., 2014). Other investigations showed further that erinacine-enriched HE mycelium was not teratogenic in Sprague-Dawley rats with doses up to 2625 mg/kg (Li, Chen, et al., 2018).
Neuroprotective activities
Neurotrophic factors are essential to maintain and organize the functionality of neurons (Obara et al., 1999) as neurons cannot proliferate and regenerate as terminally differentiated cells. Therefore, glial cells support neurons by releasing neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic (BDNF), and others. Amongst these neurotrophic factors, NGF has been extensively investigated. It has a wide range of effects on neurons such as the induction of neuronal differentiation, the promotion of neuronal survival and the prevention of apoptosis in neurons of both central and peripheral origin. Interestingly, it has been shown that NGF synthesis in glial cells is amplified following the stimulation of b-adrenoceptors (Mocchetti et al., 1989). However, the detailed mechanism and factors leading to NGF synthesis are still under investigation.
Due to their beneficial effects on neuronal development, neurotrophic factor-like substances or their inducers are expected to be beneficial for the treatment of neuronal diseases. In this context, medicinal mushrooms (MMs) have received much attention from the scientific community and in particular HE has become a promising candidate for the development of an approach to target a variety of human diseases related to neurological degeneration. In fact, various bioactive compounds extracted from HE have been shown to recover, or at least ameliorate, a wide range of pathological brain conditions such as Alzheimer’s disease, depression, Parkinson’s disease, and spinal cord injury (Brandalise et al., 2023).
In a large body of in vitro and in vivo preclinical studies, bioactive compounds from HE have been correlated with an increase in the production of neurotrophic factors in the central nervous system (CNS). Interestingly, HE contains various constituents such as hericenones and erinacines that have been identified to stimulate nerve growth factor (NGF) synthesis. For instance, Shimbo et al. examined the effects of erinacine A on the production of NGF in rats and found increased levels of both noradrenaline and homovanillic acid, as well as NGF in various brain regions (Shimbo et al., 2005). Likewise, hericenone E was reported to stimulate NGF synthesis in rat pheochromocytoma (PC12) leading to a NGF secretion which was two-fold higher than the positive control applied in the study (Phan et al., 2014). Beyond that, in another study conducted with Hericium coralloides (HC), corallocins with an NGF and/or BDNF inducing effect were identified (Wittstein et al., 2016). An in vitro study conducted by Mori and colleagues examined the effects of ethanol extracts of four edible mushrooms in human astrocytoma cells and found that only the HE extract promoted NGF mRNA expression in a concentration-dependent manner. Within the same study the efficacy of HE was examined in vivo. Mice given feed containing 5% HE dry powder for 7 days showed an increase in the level of NGF mRNA expression in the hippocampus (Mori et al., 2009). Based on this and other studies showing positive effects of Hericium on NGF synthesis (Chun-Yi et al., 2015; Kawagishi et al., 1992), its intake has been hypothesized to have potential beneficial effects on brain function and the autonomic nervous system.
While most of all hericenones show stimulating activity for the biosynthesis of NGF in astrocytes, hericenone B has been reported to be effective for the protection from cerebrovascular disturbance (Mori et al., 2010). This function might also contribute to an improvement of cognitive functions because cerebral blood flow is regarded as an important factor to dementia. Likewise, HE mycelia, and its isolated diterpenoid derivative, erinacine A, reduced infarction by 22% at 50 mg/kg and 44% at 300 mg/kg in an animal model of global ischemic stroke. Results of this study suggested further, that this effect was partially mediated by its ability to reduce cytokine levels (J. Zhang et al., 2016).
Myelin sheaths are lipid-rich bio-membranes that wrap neuronal axons to insulate them and increase the rate at which electrical impulses pass along the axon. Hence, injury of the myelin structure leads to an impairment and severe illness of the nerve system. HE has been recognized to have an effect on nerve tissue in vitro. Its extracts from 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).
HE can further regulate the growth and development of neurons and accessory structures and has been reported to contain neuroactive compounds that stimulate neurite outgroth in vitro. For instance, polysaccarides purified from the liquid culture broth of HE mycelium enhance the growth of rat adrenal nerve cells and the extension of the neurites of PC12 cells (Park et al., 2002). Its efficacy was even found to be higher than those from known nerve growth factors such as Nerve Growth Factor (NGF) and Brain-Derived Nerve Factor (BDNF). Likewise, in a study using a neural hybride clone cell line, aqueous extracts of fruit bodies and mycelium were found to induce neurit outgrowth in cultured cells (K.-H. Wong et al., 2007). Beyond that, Wong et al. investigated the possible use of aqueous extract of HE fruiting bodies in the treatment of axonotmetic peroneal nerve injury in adult female Sprague–Dawley rats by daily oral administration, and the data suggested that the extract could promote the regeneration of injured rat peroneal nerve in the early stage of recovery (K.-H. Wong et al., 2011).
Previous research has shown that levels of NGF are significantly lower in patients with major depressive disorder than in healthy subjects (Chen et al., 2015). HE constituents leading to the expression of neurotrophic factors, have therefore been suggested in the treatment of depression.
A study by Ryu et al. in 2018 investigated the antidepressant and anxiolytic effects of HE ethanolic extract in adult mice and found that chronic administration of a high dose (60 mg/kg) HE extract significantly reduced the time spent in the peripheral region of the open field test, suggesting a potential anxiolytic effect (Ryu et al., 2017). Furthermore, immobility time was significantly reduced in both the tail suspension test and forced swim test, indicating an anti-depressant-like effect. Histological examinations of the mice revealed further, that extracts of H. erinaceus had increased both, NGF mRNA and protein expression in the hippocampus, indicating the bioactive compounds from HE extract could pass through the blood–brain barrier leading to hippocampal neurogenesis (Ryu et al., 2017). Similarly, Vigna et al. found in a study conducted in subjects affected by overweight or obesity under a low calorie diet regimen, that eight weeks of oral HE supplementation could decrease depression, anxiety, and sleep disorders (Vigna et al., 2019). They found further that these effects were associated with a change in peripheral pro-BDNF and in the pro-BDNF/BDNF ratio. Already back in 2015, Yao et al. reported an antidepressant-like and anti-inflammatory effects of an extract obtained from the fruting bodies of HE in an animal model of depression with LPS-induced inflammation (Yao et al., 2015). The HE extract was administered orally to mice 60 min before the intraperitoneal injection of LPS, and behavioral tests were performed 24 h after LPS injection. They found that acute treatment with the HE extract significantly reduced the depressive-like behaviors with significant reduction of the LPS-induced immobility in both the forced swim and tail suspension tests, suggesting its neuroprotective effects against inflammation-associated depression.
Depression or anxiety were found much less frequently and were less intensive in menopausal women, who administered powdered fruitbodies of HE mushroom in comparison to the group receiving placebo (Nagano et al., 2010). Drugs with their extracts are beneficial for treating primary cognitive deficits and negative symptoms of schizophrenia (Inanaga, 2015). Moreover, administration of lion’s mane mushroom extracts in mice has led to an enhancement of learning abilities and improvement of memory (Wang LiLi et al.).
Modulation of monoamine neurotransmitters is a major therapeutic target for the treatment of depression. Chiu et al. (2018) showed that 14 days of restraint stress reduced the levels of monoamines neurotransmitters in the hippocampus of mice. Interestingly, the chronic administration of high-dose (400 mg/kg) HE mycelium extract effectively restored the depleted expression levels of serotonin, norepinephrine, and dopamine in the hippocampus of restraint stressed-animals (Chiu et al., 2018).
In clinical studies many other neuronal health-promoting effects of HE were shown (Friedman, 2015). Female students who took drugs with extracts of HE declared the improvement of the quality of sleep (Okamura et al., 2015). Oral intake of HE has been further recognized as a safe and convenient method for dementia prevention. In a randomized, double-blind, parallel-group comparative study, participants taking supplements containing fruiting bodies of HE for 12 weeks showed a significant improvement of cognitive functions. The authors of the study associated the improvement of cognitive effects with various chemical compounds in the mushroom, including hericenones (Saitsu et al., 2019). Mori et al. (Mori et al., 2011) also suggested HE to be useful in the prevention or treatment of dementia and cognitive dysfunction, as they found that dietary administration of HE powder prevented the impairments of spatial short-term and visual recognition memory induced by amyloid β(25–35) peptide in male mice. Likewise, a previous double-blinded clinical study has shown that oral administration of HE fruiting bodies was effective in improving mild cognitive impairment in 50- to 80-year-old Japanese patients (Mori et al., 2009). However, when examining the constituents of this effect, hericenones failed to stimulate NGF gene expression in primary cultured rat astroglia cells and 1321N1 human astrocytoma cells (Mori et al., 2008), suggesting that hericenones were not the sole constituents responsible for the neuroprotective activities of Hericium. On the other hand, the prominent beneficial effect of erinacine A was confirmed in the central nervous system in rats (Chen et al., 2016) and a xanthurenate and an isoindolinone from the mycelia of HE was found to possess a significant inhibition on the production of NO in LPS-activated microglia (Lin et al., 2018).
Alzheimer’s disease (AD), an age-related progressive neurodegenerative disorder, is characterized by the formation of neurofibrillary tangles, extracellular aggregated amyloid-β (Aβ) plaques, and neural and synaptic loss (Hardy & Selkoe, 2002; Murphy & LeVine, 2010). Growing evidence suggests further that Alzheimer’s disease progression becomes a runaway chain reaction after a certain point. In the presence of amyloid-β plaques, secondary injuries such as inflammation, excitotoxicity, and apoptosis may trigger the deposition of hyperphosphorylated tau proteins (L. Wang et al., 2016). Once the process starts, the tau tangles are unabated even after the removal of amyloid-β plaques. Moreover, studies in transgenic amyloid precursor protein (APP) mice have shown that therapies are most effective when administered before plaque formation (Das et al., 2012; L. Wang et al., 2016). Amyloid-β is therefore an ideal therapeutic target for primary prevention. However, despite the urgent need for new treatments the Alzheimer’s disease drug development pipeline of the pharmaceutical industry is characterized by a small number of drug candidates and a high rate of failure. Between 2002 and 2012 potential drug candidates for Alzheimer’s had a failure rate of 99.6%. Moreover, the number of drugs entering the pipeline has been declining since 2009 (Cummings et al., 2014).
In one study, transgenic mice with an induced Alzheimer’s-like condition, were utilized to evaluate the therapeutic effect of HE mycelia containing 19 mg/g erinacine A. After 30 days of oral administration, the erinacine A-enriched mycelia were able to attenuate cerebral Aβ plaque burden, prevent recruitment and activation of plaque-associated microglia and astrocytes, promote the expression of insulin degrading enzyme, increase the NGF-to-NGF precursor (proNGF) ratio, and enhance the proliferation of neuron progenitors and the number of newly born neurons in the dentate gyrus region (Tsai-Teng et al., 2016). In line with that, another study showed the therapeutic potential of erinacine S and erinacine A isolated from the mycelia of HE in Alzheimer’s disease. Application of the isolated substances in a 30-day oral course attenuated Aβ plaque burden in the brains of 5-month-old female APP/PS1 transgenic mice. Moreover, erinacines A and S significantly increased the level of insulin-degrading enzyme in cerebral cortex (Chen et al., 2016).
Beyond that, preclinical studies in rats have shown that there can be improvements in ischemic stroke, Parkinson’s disease, Alzheimer’s disease, and depression if HE mycelia enriched with erinacines are included in daily meals (Li, Lee, et al., 2018). Consistently, various other pre-clinical and clinical studies have demonstrated that HE significantly ameliorates depressive disorder through monoaminergic modulation, neurogenic/neurotrophic, and anti-inflammatory pathways, indicating the potential role of HE as complementary and alternative medicine for the treatment of depression (Chong et al., 2019).
Anti-cancerous and immuno-modulating activities
Over the last decades multiple studies have demonstrated the anti-cancerous potential of HE mushrooms. In a study conducted back in 2001 water and ethanol extracts of the mycelium and fruiting body of HE were used in an Ames test to screen for antimutagenic effects against known mutagens (J. C. Wang et al., 2001). Both extracts were found to have a stronge antimutagenic activity that was produced in a concentration-dependent manner. Interestingly, the extracts from the fruiting body had better antimutagenic effects than the ones from the mycelium. Due to their ability to induce apoptosis (programmed cell death) in U937 human monocytic leukemia cells, HE extracts have further been linked with a therapeutic potential against human leukemia (S. P. Kim et al., 2011). Moreover, a corallocin identified in Hericium coralloides (HC) showed antiproliferative activity in human cancer cell lines (Wittstein et al., 2016).
A meachnism that is responsibel for the anti-cancer activities of HE is immuno-modulation. Wang et al. studied anti-tumor and immuno-modulation activity of polysaccharides extracted from the culture broth of HE in mice (JinnChyi Wang et al., 2001). Their results revealed that the isolated polysaccharides had significant anti-artificial pulmonary metastatic tumor effects. Moreover, they reported that the polysaccharides enhanced the increase of CD4+ T cells and macrophages. Liu et al. reported the antitumor activity and immunity regulating effects of the polysaccharides of HE in mice burdened with a sarcoma (C. Liu et al., 2000). In a study by Lee et al., the crude water-soluble polysaccharide of HE up-regulated some functional immuno-modulating events mediated by activated macrophages, such as production of nitric oxide (NO) and expression of cytokines (IL-1β and TNF-β), which might be responsible for the anticancerous properties of the mushroom (Lee et al., 2009).
Another study that investiated water extract from HE, demonstrated its ability to activate macrophages and to induce nitric oxide (NO) production in macrophages (Son et al., 2006). In particular, larger Polysaccharides from H. erinaceus have been shown to increase the levels of T cells and macrophages in mice (J. C. Wang et al., 2001). They are also reported to induce the dendritic cell activation and modulate the TH1 immune response in mice (Sheu et al., 2013), as well as triggering a maturation of human dendritic cells from human peripheral blood (S. K. Kim et al., 2010). Dendritic cells are professional antigen-presenting cells that can interact with polysaccharides to bridge innate and adaptive immunity. Upon activation, antigens are processed and presented by dendritic cells that express high levels of costimulatory and major histocompatibility complex (MHC) molecules. Dendritic cells also secrete various cytokines and chemokines to modulate T and B lymphocyte responses.
Antioxidant activities
Reactive oxygen species (ROS) can cause oxidative stress which may leads to a variety of diseases and promote the aging process. Under oxidative stress, free radicals or various ROSs can be products that are capable of damaging tissues, and functional cell components such as DNA, protein and lipids of host organisms. Antioxidant molecules are therefore beneficial as they inhibit oxidation reactions and eliminate free radicals (Krishnaiah et al., 2011).
Polysaccharide isolated from HE showed a strong antioxidant activity in vitro and potent hepatoprotective effect in vivo, with the hepatoprotective effect likely to be associated with the antioxidant capacity of the isolated polysaccharides (Z. Zhang et al., 2012). Correspondingly, Wang et al. found that extracellular and intracellular polysaccharides had a protective effect on oxidative hepatotoxicity in mice (K. Wang et al., 2015). Moreover, polysaccharides from HE can significantly increase antioxidant enzymes activities and decrease the lipid peroxidation level and ischemia reperfusion-induced oxidative kidney injury in experimental animals (Han et al., 2013).
Many researchers assume that the potential hepatoprotective effect of HE observed in vivo relates to its antioxidant capacity. HE has the potential to induce apoptosis of human hepatocellular carcinoma cells (Lee & Hong, 2010). Hence, dietary supplementation with HE could restrain the hepatic damage caused by acute alcohol exposure (Z. Liu et al., 2015).
An investigation in rats has further shown, that HE polysaccharides significantly enhance skin antioxidant enzymes activities and collagen protein levels in a dose-dependent manner, which led the authors of the study to conclude that HE polysaccharides pose anti-skin-aging activities (Xu et al., 2010). In addition, HE extracts have shown to attenuate diabetic neuropathy in rats, with the antioxidant activity of extracts being the probable way by which the diabetic neuropathy has been alleviated (Yi et al., 2015).
Other therapeutic activities
In a study conducted by Wang et al, extracts of HE were found not only to have a hypoglycemic effect but also to reduce the elevation rates of serum triglyceride and total cholesterol levels when administered to streptozotocin-induced diabetic rats (Jinn Chyi Wang et al., 2005). On the other hand, in an in vitro study conducted with Peripheral blood mononuclear cells (PBMCs) isolated from older adults, extracts from Hericium coralloides (HC) have been found to exert immunomodulatory effects on innate immunity. This may be beneficial in conditions where allergic inflammation is present, including asthma, allergic rhinitis, and eczema (Williams et al., 2023).
Antifungal and biofilm preventative compounds were identified in various in vitro assay examining extracts from the fruiting body and mycelial of a Hericium mushroom collected in North America (Song et al., 2020). In this study it was further recognized that the used cultivation media significantly influenced the production of secondary metabolites.
The cytoprotective effects of HE freeze-dried fruiting bodies have been shown to be effective against ethanol-induced gastric mucosal injury in rats (M. 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 (M. A. Abdulla et al., 2011). HE 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 (J.-Y. Wong et al., 2013).
The methanol extract from HE cultivated with Artemisia changes the expressions of typical liver enzymes and the hepatic structure, which implies that the extract has a strong protective effect on CCl4-induced hepatic damage in rats (Choi et al., 2005). Moreover, extracts of HE protected mice infected with a sublethal dose of Salmonella Typhimurium against necrosis of the liver, a biomarker of in vivo salmonellosis (S. P. Kim et al., 2012).