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Improvement of cognitive functions by oral intake of Hericium erinaceus

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Abstract

Hericium erinaceus has been recognized as medical mushroom since ancient time, but its scientific evidence for human health has been still uncertain. In this study, we tested a randomized, double-blind, placebo-controlled parallel-group comparative study to evaluate the improvement of the cognitive functions by taking supplements containing fruiting body of H. erinaceus for 12 weeks. We performed three kinds of tests: Mini Mental State Examination (MMSE), Benton visual retention test, and Standard verbal paired-associate learning test (S-PA). MMSE alone showed that oral intake of H. erinaceus significantly improved cognitive functions and prevented from the deterioration. We speculate that various chemical compounds, including hericenones, in the mushroom have multiple effects to the brain neural networks and improve cognitive functions. Oral intake of H.erinaceus is safe and convenient method for dementia prevention so far.

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... A 12-week parallel intervention study in 31 cognitively healthy adults allocated to consume either a combination of an extract of Eleutherococcussenticosus (ES) and rhizomes of Drynariafortunei (DR) (203.01 mg/d of ES leaf extract, and 20.01 mg/d of DR), showed significant improvements in language, semantic fluency and figure recall scores [75]. Consumption of Hericiumerinaceus supplement (3.2 g/d) for 12 weeks also improved cognitive function and prevented cognitive decline in a study of 34 cognitively healthy subjects over the age of 50 years [76]. The effect of fermented Laminaria japonica was also evaluated in 60 moderately active senior subjects randomized to consume either 1.5 g/d of this supplement or a sucrose pill as placebo. ...
... Other dietary supplements that have shown significant improvements on different cognitive domains are fungi and algae extracts (Hericiumerinaceus, Tremella fuciformis and Laminaria japonica), other plant extracts (Eleutherococcussenticosus leaf, Drynariafortuneirhizome, combined sage, rosemary and melissa, auraptene, astaxanthin and matured hop bitter acids), minerals such as magnesium, medium-chain triglycerides and the complex Twendee X (supplement containing a mix of eight antioxidants). The consumption of the above antioxidant and anti-inflammatory supplements not only significantly improved subjective memory complaints [84] and scores in different cognitive domains such as psychomotor and processing speed [73], working memory [76,77,79,81], short-term memory [74,76,77,84], spatial working memory [75,79,81,87], verbal episodic memory [78], verbal fluency [75,82,83], language [75,79,81,87], executive functions [79,82,84] and attention [79,83,87], but also cortical gray matter integrity in AD-related brain regions [84]. The spermidine-rich plant extract also had an impact on memory performance in subjects with SCD, although this was not significant, probably due to the small sample size (n = 30) and/or the short follow-up period (3 months) [85]. ...
... Other dietary supplements that have shown significant improvements on different cognitive domains are fungi and algae extracts (Hericiumerinaceus, Tremella fuciformis and Laminaria japonica), other plant extracts (Eleutherococcussenticosus leaf, Drynariafortuneirhizome, combined sage, rosemary and melissa, auraptene, astaxanthin and matured hop bitter acids), minerals such as magnesium, medium-chain triglycerides and the complex Twendee X (supplement containing a mix of eight antioxidants). The consumption of the above antioxidant and anti-inflammatory supplements not only significantly improved subjective memory complaints [84] and scores in different cognitive domains such as psychomotor and processing speed [73], working memory [76,77,79,81], short-term memory [74,76,77,84], spatial working memory [75,79,81,87], verbal episodic memory [78], verbal fluency [75,82,83], language [75,79,81,87], executive functions [79,82,84] and attention [79,83,87], but also cortical gray matter integrity in AD-related brain regions [84]. The spermidine-rich plant extract also had an impact on memory performance in subjects with SCD, although this was not significant, probably due to the small sample size (n = 30) and/or the short follow-up period (3 months) [85]. ...
Article
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New dietary approaches for the prevention of cognitive impairment are being investigated. However, evidence from dietary interventions is mainly from food and nutrient supplement interventions, with inconsistent results and high heterogeneity between trials. We conducted a comprehensive systematic search of randomized controlled trials (RCTs) published in MEDLINE-PubMed, from January 2018 to July 2021, investigating the impact of dietary counseling, as well as food-based and dietary supplement interventions on cognitive function in adults with or without cognitive impairment. Based on the search strategy, 197 eligible publications were used for data abstraction. Finally, 61 articles were included in the analysis. There was reasonable evidence that dietary patterns, as well as food and dietary supplements improved cognitive domains or measures of brain integrity. The Mediterranean diet showed promising results, whereas the role of the DASH diet was not clear. Healthy food consumption improved cognitive function, although the quality of these studies was relatively low. The role of dietary supplements was mixed, with strong evidence of the benefits of polyphenols and combinations of nutrients, but with low evidence for PUFAs, vitamin D, specific protein, amino acids, and other types of supplements. Further well-designed RCTs are needed to guide the development of dietary approaches for the prevention of cognitive impairment.
... Du ring another study conducted in 2019 the participants ate cakes containing the Lion's mane during a 3 months' period. The results of this experiment show ed an improvement of cognitive functions and a significant inhibition of short-term memory disorders [25]. The fact that the Lion's mane contains active chemical compounds stimulating production of nerve growth factor (NGF), is well known [26]. ...
... W innym badaniu z 2019 roku uczestnicy, przez okres 3 miesięcy, otrzymywali ciastka zawierające Lwią grzywę. Wyniki przeprowadzonego eksperymentu wykazały poprawę funkcji poznawczych oraz istotne zahamowanie zaburzeń pamięci krótkotrwałej [25]. Wiadomo, że Lwia grzywa zawiera aktywne związki, które stymulują produkcję czynnika wzrostu nerwów (NGF) [26]. ...
Article
Physically active people and athletes always seek new dietary interventions in­cluding natural products, hoping to improve their condition and gain support, allowing them to meet their settled goals. Potential benefits of using medicinal mushrooms (ganotherapy), resulting from their proven efficacy, seem extremely promising for athletic performance. They may evoke a justified interest, especially among competitors from western countries where the tradition of using mushrooms for health reasons is virtually nonexistent. The goal of the paper is to present the current knowledge of selected medicinal mushrooms among the population involved in excessive physical exercise and the range of research in the above-mentioned domain.
... In a more recent double-blind, placebo-controlled study assessing the effect of lion's mane on cognitive function, healthy older adults over 50 years of age (n=31) were randomized for 12 weeks to either 4 times/day dose of 0.8 g of lion's mane (3.2 g/day total; n=16) or placebo (n=15) [67]. Cognitive function was assessed at baseline and 6 and 12 weeks using the MMSE, the Benton visual retention test, and the Standard verbal paired-associate learning test. ...
... In addition to various diseases and disorders, nutrients and phytonutrients have been examined for their efficacy on cognitive function in healthy adults. For example, Bacopa monnieri has been studied in a few instances in healthy populations of various ages and shows promise in improving several domains of cognitive function with minimal recorded adverse effects [35,[37][38][39][40]. Lion's mane also showed a significant improvement in cognitive function in older adults after 12 weeks of consumption [67]. Furthermore, Rhodiola rosea has shown hopeful results in improving mental capacity for work, fatigue, anxiety, mood, and cognitive performance in healthy adults [194][195][196][197][198]. ...
Article
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Background and aim: Brain health is becoming more important to the average person as the number of people with cognitive impairments, such as Alzheimer's disease (AD), is rising significantly. The current Food and Drug Administration-approved pharmacotherapeutics for dementia neither cure nor halt cognitive decline; they just delay the worsening cognitive impairment. This narrative review summarizes the effects of nutrients and phytonutrients on cognitive function. Methods: A comprehensive literature search of PubMed was performed to find clinical trials in humans that assessed the effects of nutrients and phytonutrients on cognitive function published in English between 2000 and 2021. Six independent reviewers evaluated the articles for inclusion in this review. Results: Ninety-six articles were summarized in this narrative review. In total 21 categories of nutrients and phytonutrients were included, i.e., α-lipoic acid, Bacopa monnieri, B vitamins, cholinergic precursors, vitamin D, vitamin E, Ginkgo biloba, ginseng, lion's mane mushroom, N-acetyl cysteine, omega-3 fatty acids, aloe polysaccharides, Rhodiola rosea, rosemary, saffron, tart cherries, turmeric, wild yam, Withania somnifera, xanthines, and zinc. Particular noteworthy effects on cognition included memory, recollection, attention, intelligence, vocabulary, recognition, response inhibition, arousal, performance enhancement, planning, creative thinking, reaction time, vigilance, task switching, orientation to time, place, and person, reading, writing, comprehension, accuracy, learning, information processing speed, executive function, mental flexibility, daily functioning, decrease in mental fatigue, and freedom from distractibility. Some nutrients and phytonutrients also improved mood and contentedness and reduced anxiety and the need for caregiving. These effects are not completely consistent or ubiquitous across all patient populations or health statuses. Adverse effects were minimal or nonexistent. Conclusion: Due to the growing population of people with cognitive impairment and the lack of effective pharmacotherapeutics, it is prudent for those afflicted or their caregivers to find alternative treatments. Our narrative review shows that many of these nutrients and phytonutrients may be promising for treating some aspects of cognitive impairment, especially for people afflicted with AD. Relevance for patients: As demonstrated in a number of clinical trials, healthy adults and patients with various health challenges (e.g., AD, mild cognitive impairment, multiple sclerosis, and Parkinson's disease) exhibiting a wide range of severity in cognitive defects would be best served to consider multiple nutrients and phytonutrients to improve aspects of their cognitive function.
... Recent studies focus on the pharmacology and feasibility of bioactive compounds of plant and fungal origin as a potential strategy to target a variety of human metabolic and brain disorders [37]. The mechanism and possible synergy of action of these compounds has not been studied yet, however mushrooms-derived products with potential neuroprotective and psychotropic activities can prevent and mitigate development of mental disorders, including depression, anxiety, sleep disturbances and cognitive alterations [1, 7, 8, 12-14, 20, 21-24]. ...
... The cultivated edible mushroom, H. erinaceus is an important medicinal fungus with immunomodulatory, anti-mutagenic, antioxidant, anti-inflammatory and antitumor properties. Myco-pharmacological studies have attracted considerable attention on H. erinaceus as a neuroprotector to prevent NDD, including dementia, anxiety or depression [7,13,20,25,[35][36][37][38]. ...
Article
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Badalyan S.M. et Rapior S. Agaricomycetes medicinal mushrooms with potential potential neuroprotective activity growing in rmenia. Proceedings of the Yerevan State University, Chemistry and Biology, 54 (3), 196-203 (2020). hal-03090953 _____ The Agaricomycetes mushrooms (phylum Basidiomycota) are recognised sources of valuable food and medicines. They are producers of bioactive compounds (phenolics, polysaccharides, proteins, steroids, terpenoids, etc.) possessing around 130 therapeutic effects (antimicrobial, anti-inflammatory, antioxidant, immunomodulatory, etc.). Mushrooms are also reported as potential neurotrophic and neuroprotective agents. Seventeen edible and inedible agaricomycetous species from different taxonomic and ecological groups have been reported in Armenia to possess neuroprotective activity. Evaluation resource value and biotechnological potential of Armenian agaricomycetous mushrooms will assist further development of novel myco-pharmaceuticals to prevent and mitigate different disorders, including neurodegenerative.
... Hericium erinaceus was found to have beneficial effects on cognition or mild cognitive impairment in several studies. 58,59 A combination of Ophiocordyceps sinensis and G. lucidum did not, however, enhance cognitive function in young healthy participants. 60 Psilocybin mushrooms have been studied mostly for their mind-altering properties, although they appear to have potential for the treatment of depression. ...
Article
Mushrooms are valued by humans worldwide as food, but also for their medicinal properties. Over 130 medicinal effects of mushrooms have been reported, including anti-diabetic, antioxidant, antimicrobial, anticancer, prebiotic, immunomodulating, anti-inflammatory and cardiovascular benefits. Several mushrooms have been tested in phase I, II, or III clinical trials for various diseases, including cancers, as well as to modulate immunity. Here, we review clinical studies on medicinal mushrooms or preparations (but not pure compounds) derived thereof. Overall, few phase III trials have been performed, and in many cases, these trials included a relatively small number of patients. Therefore, despite the promising published clinical data, especially on immune modulation, more work is required to clarify the therapeutic value of mushrooms.
... Ma et al. 2010;Nagano et al. 2010;Mori et al. 2011;Kim et al. 2014;Phan et al. 2014a Phan et al. , b, 2019Thongbai et al. 2015;Cheng et al. 2016;Kuo et al. 2016;Zhang et al. 2016a;Spelman et al. 2017;Chong et al. 2019;Jang et al. 2019;Kushairi et al. 2019;Saitsu et al. 2019;Üstün and Ayhan 2019;Limanaqi et al. 2020;Yadav et al. 2020). ...
Book
Diversity of wild and cultivated macrofungi as edible and medicinal mushrooms has long been known by humans as a source of valuable food and medicines used by tradipraticians. In the fungal kingdom, macrofungi taxonomically belong to two phyla, the Basidiomycota (class Agaricomycetes) and Ascomycota (class Pezizomycetes). Macrofungi have been used in traditional Asian and European Medicines, and based on 90,000 known worldwide distributed mushroom species, are considered an important resource for modern clinical and pharmacological research. They are regarded as a source of high- and low-molecular-weight bioactive compounds (alkaloids, lipids, phenolics, polysaccharides, proteins, steroids, terpenoids, etc.) with more than 130 therapeutic effects (anti-inflammatory, antimicrobial, antioxidant, antitumor, antiviral, cytotoxic, hepatoprotective, hypocholesterolemic, hypoglycemic, hypotensive, immunomodulatory, etc.). There is also scientific evidence of using macrofungi as neuroprotectants, that is, Agaricus blazei (= Agaricus subrufescens), Ganoderma lucidum, Grifola frondosa, Hericium erinaceus, Pleurotus ostreatus, and Trametes versicolor. However, their neuroprotective effects have not been fully explored. This review discusses recent advances in research on the neuroprotective potential of macrofungi and perspectives for their application as neuroprotectants in biomedicine to prevent, support, or cure neurodegenerative disorders.
... Ma et al. 2010;Nagano et al. 2010;Mori et al. 2011;Kim et al. 2014;Phan et al. 2014a Phan et al. , b, 2019Thongbai et al. 2015;Cheng et al. 2016;Kuo et al. 2016;Zhang et al. 2016a;Spelman et al. 2017;Chong et al. 2019;Jang et al. 2019;Kushairi et al. 2019;Saitsu et al. 2019;Üstün and Ayhan 2019;Limanaqi et al. 2020;Yadav et al. 2020). ...
Chapter
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Badalyan S.M. et Rapior S. The neurotrophic and neuroprotective potential of macrofungi. In: Medicinal Herbs and Fungi – Neurotoxicity vs. Neuroprotection. Agrawal D.C. et Dhanasekaran M. (Eds). Publisher Springer. Chapter 2: 37-78 (2021). doi:10.1007/978-981-33-4141-8_2 ____ Diversity of wild and cultivated macrofungi as edible and medicinal mushrooms has long been known by humans as a source of valuable food and medicines used by tradipraticians. In the fungal kingdom, macrofungi taxonomically belong to two phyla, the Basidiomycota (class Agaricomycetes) and Ascomycota (class Pezizomycetes). Macrofungi have been used in traditional Asian and European Medicines, and based on 90,000 known worldwide distributed mushroom species, are considered an important resource for modern clinical and pharmacological research. They are regarded as a source of high- and low-molecular-weight bioactive compounds (alkaloids, lipids, phenolics, polysaccharides, proteins, steroids, terpenoids, etc.) with more than 130 therapeutic effects (anti-inflammatory, antimicrobial, antioxidant, antitumor, antiviral, cytotoxic, hepatoprotective, hypocholesterolemic, hypoglycemic, hypotensive, immunomodulatory, etc.). There is also scientific evidence of using macrofungi as neuroprotectants, that is, Agaricus blazei (= Agaricus subrufescens), Ganoderma lucidum, Grifola frondosa, Hericium erinaceus, Pleurotus ostreatus, and Trametes versicolor. However, their neuroprotective effects have not been fully explored. This review discusses recent advances in research on the neuroprotective potential of macrofungi and perspectives for their application as neuroprotectants in biomedicine to prevent, support, or cure neurodegenerative disorders. Corresponding authors: s.badalyan@ysu.am, sylvie.rapior@umontpellier.fr
... Several clinical trials using the fruiting bodies of the fungus have demonstrated the antidementia effect of this fungus (Kasahara, Kaneko and Shimizu 2001;Mori et al. 2009;Nagano et al. 2010;Ohtomo, Shimizu and Komatsu 2011;Saitsu et al. 2019). Very recently, in order to investigate the efficacy and safety of mycelia of the fungus enriched with 5 mg/g erinacine A (7), a clinical trial study was conducted. ...
Article
Hericium erinaceus (Yamabushitake in Japan) is a well-known edible and medicinal mushroom. We discovered antidementia compounds, hericenones C to H, from the fruiting bodies and erinacine A to I from the cultured mycelia of the fungus. Based on the data of the compounds, several clinical experiments were performed using the fungus. “Fairy rings” is a phenomenon that turfgrass grows more prolific or inhibited than the surrounding area as a ring and then occasionally mushrooms develop on the ring. We found fairy-ring causing principles “fairy chemicals” and the biosynthetic routes of the compounds on the purine metabolic pathway in plants and mushrooms.
... Recently, in a randomized, double-blind, placebo-controlled parallel-group, comparative study, the administration of a supplement containing Lion's mane mushroom fruiting body showed improvement of Mini-Mental State Examination (MMSE) scores among 16 healthy participants over 50 years old in the intervention group, compared with 15 participants in the placebo group (p = 0.0328) (Saitsu et al., 2019). However, Benton visual retention test and Standard verbal paired-associate learning test (S-PA) scores were not statistically different in the intervention group compared with placebo during follow up (ad-interim and ex-post) of 12 weeks. ...
Article
Background mushrooms are traditionally used as a food ingredient and in folk medicine. Many in vitro and animal studies have reported their potential health effects, but without any clear application in human health. Although they have a worldwide history of use in dishes and folk medicine, mushroom extracts are commonly taken as supplements but need to be evaluated regarding clinical effects and safety, in particular among patients searching for further efficacy for their disease beside pharmacological treatments already prescribed. Scope and approach this review summarizes available data from the scientific literature about the nutritional and effects of mushrooms on human health by selecting clinical studies on humans in English. At the same time, the safety profile and unwanted effects were highlighted. Key findings and conclusions in spite of their wide use among populations, data on humans were scant and did not justify extensive use without more well-designed trials on mushroom efficacy. Overall, their use seems to be safe, but with some side effects, easily reversible after intake interruption. Nutritional use seems promising for coping with the energy surplus of the Western countries and could be useful for some nutritional aspects.
... In another randomized, double-blind placebo-controlled study, administration of 0.5 g H. erinaceus fruiting body in cookies over 4 weeks showed a reduction in anxiety and depression in menopausal women (n = 30) compared to those taking placebo, as measured by the Center for Epidemiologic Studies Depression Scale and Indefinite Complaints Index (Nagano et al., 2010). In the third randomized, double-blind, placebo-controlled parallelgroup comparative study, the consumption of cookies containing 0.8 g of H. erinaceus fruiting body dry powder alleviated the deterioration of short memories and improved the cognitive functions in 31 participants with an average age of 61.3 years old over the period of 12 weeks, as measured by MMSE (Saitsu et al., 2019). Prior studies have reported that NGF could enhance neurogenesis-inducing effects, which led to antidepressant and antianxiety activities (Shohayeb et al., 2018). ...
Article
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Objective To investigate the efficacy and safety of three H. erinaceus mycelia (EAHE) capsules (350 mg/capsule; containing 5 mg/g erinacine A active ingredient) per day for the treatment of patients with mild Alzheimer’s Disease (AD).Methods This study comprised a 3-week no-drug screening period, followed by a 49-week double-blind treatment period with 2-parallel groups in which eligible patients were randomized to either three 5 mg/g EAHE mycelia capsules per day or identical appearing placebo capsules. Cognitive assessments, ophthalmic examinations, biomarker collection, and neuroimaging were followed throughout the study period.ResultsAfter 49 weeks of EAHE intervention, a significant decrease in Cognitive Abilities Screening Instrument score was noted in the placebo group, a significant improvement in Mini-Mental State Examination score was observed in the EAHE group and a significant Instrumental Activities of Daily Living score difference were found between the two groups. In addition, EAHE group achieved a significantly better contrast sensitivity when compared to the placebo group. Moreover, only the placebo group observed significantly lowered biomarkers such as calcium, albumin, apolipoprotein E4, hemoglobin, and brain-derived neurotrophic factor and significantly elevated alpha1-antichymotrypsin and amyloid-beta peptide 1–40 over the study period. Using diffusion tensor imaging, the mean apparent diffusion coefficient (ADC) values from the arcuate fasciculus region in the dominant hemisphere significantly increased in the placebo group while no significant difference was found in the EAHE group in comparison to their baselines. Moreover, ADC values from the parahippocampal cingulum region in the dominant hemisphere significantly decreased in the EAHE group whereas no significant difference was found in the placebo group when compared to their baselines. Lastly, except for four subjects who dropped out of the study due to abdominal discomfort, nausea, and skin rash, no other adverse events were reported.Conclusion Three 350 mg/g EAHE capsules intervention for 49 weeks demonstrated higher CASI, MMSE, and IADL scores and achieved a better contrast sensitivity in patients with mild AD when compared to the placebo group, suggesting that EAHE is safe, well-tolerated, and may be important in achieving neurocognitive benefits.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04065061.
... Moreover, confirm the safety of H.erinaceous and could be used in dementia prevention. 5 Another recent Italian study in 2019 on mice reported that two-month of oral intake of H.erinaceous reversed the decline of age and restore cognition memory, which means this mushroom could have neurogenesis effect. 6 In line with a vitro study conducted in Malaysia showed that Lion's Mane mushrooms contain neurotrophic factors (hericenones and erinacines) which might induce nerve growth factors essential for the maintenance of optimum neural body structure to operate. ...
Article
Background It is essential to detect morphological changes in the brain prior to the onset of cognitive decline. Although hippocampal volumes have been reported to be correlated with scores on neuropsychological tests, this relationship is still unclear among Japanese, non-demented older adults. Thus, this exploratory retrospective study aimed to identify neuropsychological tests that correlate with the degree of hippocampal atrophy in Japanese non-demented older adults. Methods Thirteen non-demented Japanese older adults aged 71.2±5.2 years were included. Hippocampal atrophy was evaluated by assessing the participants’ MRI scans using the voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) software. Spearman’s partial correlation analyses were conducted to reveal relationships between VSRAD scores and neuropsychological test scores, including Raven’s Colored Progressive Matrices test (RCPM), the Standard Verbal Paired Associates Learning test (SP-A), and the Trail Making Test (TMT) scores by controlling for age, sex, and years of education. Results The Spearman’s partial correlation analysis results revealed that there were significant correlations between the degree of hippocampal atrophy and RCPM (Rho = -0.691, P = 0.027), TMT part B (Rho = 0.823, P = 0.003), and the related SP-A test scores (Rho = -0.691, P = 0.027). Conclusions Our results indicate that neuropsychological tests, particularly the TMT part B, might be used in assessing the degree of hippocampal atrophy in non-demented Japanese elderly individuals and should be studied further in the future to develop screening methods to detect brain atrophy.
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In this study, 2-chloro-1,3-dimethoxy-5-methylbenzene (CDM), a natural product with anti-Candida albicans activity, was discovered from the Hericium erinaceus mycelium. The minimum inhibitory concentration of CDM was 62.5 μg/mL. Moreover, structural analogues of CDM obtained from chemical synthesis were applied to explore the structure-activity relationship (SAR) of CDM against C. albicans. It was found that methoxy groups, halogen atoms (except fluorine atoms), and methoxy-meta-position methyl groups in the structure of CDM were the key active groups. Furthermore, we investigated the anti-C. albicans mechanism of CDM. Experiments suggested that CDM destroyed the cell membrane of C. albicans, including the cytoplasmic membrane and mitochondrial membrane, and caused the accumulation of reactive oxygen species and mitochondrial dysfunction, which ultimately led to apoptosis of C. albicans. In addition, CDM had no toxicity on human normal gastric mucosal epithelial cells exposed to a concentration of 125 μg/mL. Experiments showed that CDM reduced the damage of C. albicans to the visceral tissue of infected mice and improved the survival rate of mice. Our research provides a scientific basis for the discovery of effective and safe anti-C. albicans drugs from H. erinaceus.
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The presence of a fused 5/6/7 tricyclic core characterizes the group of cyathane diterpene natural products, that include more than 170 compounds, isolated from fungi such as Cyathus africanus and Hericium erinaceus. These compounds have a common biosynthetic precursor (cyatha-3,12-diene) and can be produced bio- or hemi-synthetically, or via total syntheses. Cyathane diterpenes display a range of pharmacological properties, including anti-inflammatory (possibly through binding to the iNOS protein) and neuroprotective effects. Many cyathanes like cyahookerin C, cyathin Q and cyafranines B and G can stimulate neurite outgrowth in cells, whereas conversely a few molecules (such as scabronine M) inhibit NGF-stimulated neurite outgrowth. The main anticancer cyathanes are erinacine A and cyathins Q and R, with a capacity to trigger cancer cell death dependent on the production of reactive oxygen species (ROS). These compounds, active both in vitro and in vivo, activate different signaling pathways in tumor cells to induce apoptosis (and autophagy) and to upregulate the expression of several proteins implicated in the organization and functioning of the actin cytoskeleton. An analysis of the functional analogy between erinacine A and other natural products known to interfere with the actin network in a ROS-dependent manner (notably cucurbitacin B) further supports the idea that erinacine A functions as a perturbator of the cytoskeleton organization. Collectively, we provide an overview of the molecular diversity of cyathane diterpenes and the main mechanisms of action of the lead compounds, with the objective to encourage further research with these fungal products. The anticancer potential of erinacine A deserves further attention but it will be necessary to better characterize the implicated targets and signaling pathways.
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Hericium erinaceus , an ideal culinary-medicinal mushroom, has become a well-established candidate in promoting positive brain and nerve health-related activities by inducing the nerve growth factor from its bioactive ingredient. Among its active compounds, only erinacine A has confirmed pharmacological actions in the central nervous system in rats. Hence, this review has summarized the available information on the neurohealth properties of H. erinaceus mycelia enriched with erinacines, which may contribute to further research on the therapeutic roles of these mycelia. The safety of this mushroom has also been discussed. Although it has been difficult to extrapolate the in vivo studies to clinical situations, preclinical studies have shown that there can be improvements in ischemic stroke, Parkinson’s disease, Alzheimer’s disease, and depression if H. erinaceus mycelia enriched with erinacines are included in daily meals.
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New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.
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Hericium erinaceus (HE), an edible mushroom, has been used as a herbal medicine in several Asian countries since ancient times. HE has potential as a medicine for the treatment and prevention of dementia, a disorder closely linked with circadian rhythm. This study investigated the effects of the intake of HE extracts on behavioral rhythm, photosensitivity of the circadian clock, and clock gene mRNA expression in the suprachiasmatic nucleus (SCN), a central clock, in mice. Although the HE ethanol extract only affected the offset time of activity, the HE water extract advanced the sleep–wake cycle without affecting the free-running period, photosensitivity, or the clock gene mRNA expression in SCN. In addition, both extracts decreased wakefulness around end of active phase. The findings of the present study suggest that HE may serve as a functional food in the prevention and treatment of Alzheimer’s disease and delayed sleep phase syndrome.
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Hericium erinaceus (H. erinaceus) has a long history of usage in traditional Chinese medicine for the treatment of gastric disorders. Recently, it has become a well-established candidate in causing positive brain and nerve health-related activities by inducing nerve growth factor (NGF) from its bioactive ingredient, erinacine A. This active compound, which exists only in fermented mycelium but not in its fruiting body, increases NGF levels in astroglial cells in vitro as well as catecholamine and NGF levels in vivo. With increasing recognition of erinacine A in H. erinaceus (EAHE) mycelium improving neurodegenerative diseases, numerous products are being marketed based on these functional claims. To our knowledge, there have been no reports on the mutagenicity of EAHE prior to this paper. Hence, the present study was undertaken to determine the mutagenicity and genotoxicity effects of EAHE mycelium conducted in three standard battery of tests (reverse mutation, chromosomal aberration, and micronuclei tests) according to the latest guidelines in order to meet all international regulatory requirements and provide information on the safety of this new and promising natural remedy. Our results have indicated that EAHE mycelium did not significantly increase the number of revertant colonies in the bacterial reverse mutation test nor induce higher frequency of aberrations in the chromosome aberration test. Moreover, no statistically significant EAHE mycelium-related increase was observed in the incidence of reticulocytes per 1000 red blood cells and micronucleated reticulocytes per 1000 reticulocytes. In conclusion, the three standard battery of tests suggested that EAHE mycelium was devoid of mutagenicity and genotoxicity in the tested doses and experimental conditions.
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This review surveys the chemical and biological literature dealing with the isolation, structural elucidation and bioactivity of hericenones and erinacines from the fruiting body and mycelium of Hericium erinaceus, concentrating on work that has appeared in the literature up to December 2009.
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Context Nerve growth factor is a neurotrophic factor that promotes the survival of small fiber sensory neurons and sympathetic neurons in the peripheral nervous system. Recombinant human nerve growth factor (rhNGF) has demonstrated efficacy as treatment for peripheral neuropathy in experimental models and phase 2 clinical trials.Objective To evaluate the efficacy and safety of a 12-month regimen of rhNGF in patients with diabetic polyneuropathy.Design Randomized, double-blind, placebo-controlled phase 3 trial conducted from July 1997 through May 1999.Setting Eighty-four outpatient centers throughout the United States.Patients A total of 1019 men and women aged 18 to 74 years with either type 1 or type 2 diabetes and a sensory polyneuropathy attributable to diabetes.Interventions Patients were randomly assigned to receive either rhNGF, 0.1 µg/kg (n = 504), or placebo (n = 515) by subcutaneous injection 3 times per week for 48 weeks. Patients were assessed at baseline, 12 weeks, 24 weeks, and 48 weeks.Main Outcome Measures The primary outcome measure was a change in neuropathy between baseline and week 48, demonstrated by the Neuropathy Impairment Score for the Lower Limbs, compared between the 2 groups. Secondary outcome measures included quantitative sensory tests using the CASE IV System, the Neuropathy Symptom and Change questionnaire, the Patient Benefit Questionnaire (PBQ), and a global symptom assessment, as well as nerve conduction studies and occurrence of new plantar foot ulcers. Patients also were evaluated for presence of adverse events.Results Among patients who received rhNGF, 418 (83%) completed the regimen compared with 461 (90%) who received placebo. Administration of rhNGF was safe, with few adverse events attributed to treatment apart from injection site pain/hyperalgesia and other pain syndromes. However, neither the primary end point (P = .25) nor most of the secondary end points demonstrated a significant benefit of rhNGF. Exceptions were the global symptom assessment (P = .03) and 2 of 32 comparisons within the PBQ, which showed a modest but significant benefit of rhNGF (P = .05 for severity of pain in the legs and P = .003 for 6-month symptoms in the feet and legs).Conclusion Unlike previous phase 2 trials, this phase 3 clinical trial failed to demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy. Figures in this Article Nerve growth factor (NGF) is a protein that plays a major role in the development and maintenance of the peripheral nervous system. Nerve growth factor selectively promotes the survival of small fiber sensory neurons that mediate pain, temperature sensation, and sympathetic neurons.1 Nerve growth factor is expressed in target tissues innervated by responsive neurons, where it binds to specific high-affinity receptors and is retrogradely transported back to the neuronal cell body.2 Recent data suggest that reduced availability of NGF may play a significant role in the pathogenesis of diabetic polyneuropathy. In animals with diabetes mellitus, retrograde axonal transport of NGF is impaired,3- 5 and levels of NGF messenger RNA are reduced in neuronal target tissues.6 In patients with diabetes mellitus, levels of NGF are reduced in skin biopsy specimens. Furthermore, the diminished levels of NGF in the skin correlate with decreased skin axon-reflex vasodilatation, suggesting that reduced availability of NGF from the target tissue leads to early dysfunction of small fiber neurons.7 Systemic administration of NGF prevents manifestations of neuropathy in rodent models of toxic8- 9 and diabetic polyneuropathy.10 That loss of NGF might contribute toward the pathogenesis of diabetic polyneuropathy plus the demonstrated ability of exogenous NGF to prevent experimental neuropathy provided a compelling rationale for testing NGF administration in clinical studies. Two randomized, placebo-controlled trials of recombinant human NGF (rhNGF) administered to patients with polyneuropathy were initiated. In a phase 2 trial of 250 patients with diabetic polyneuropathy, improvements in signs and symptoms were seen after treatment with rhNGF, 0.1 or 0.3 µg/kg, subcutaneously, 3 times per week for 6 months.11 A second phase 2 trial of 270 patients with human immunodeficiency virus (HIV)–associated sensory neuropathy demonstrated significant improvements in neuropathic pain following 18 weeks of treatment with rhNGF, 0.1 or 0.3 µg/kg, twice a week.12 Recombinant human NGF was well tolerated with the exception of self-limited injection site hyperalgesia and other pain-related syndromes. This article reports the results of a large randomized, double-blind, placebo-controlled, phase 3 study of rhNGF administered to patients with diabetic polyneuropathy to determine safety and efficacy during a 12-month period.
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Hericium erinaceus (H. erinaceus) improves the symptoms of menopause. In this study, using ovariectomized mice as a model of menopause, we investigated the anti-obesity effect of this mushroom in menopause. Mice fed diets containing H. erinaceus powder showed significant decreases in the amounts of fat tissue, plasma levels of total cholesterol, and leptin. To determine the mechanism, groups of mice were respectively fed a diet containing H. erinaceus powder, a diet containing ethanol extract of H. erinaceus, and a diet containing a residue of the extract. As a result, H. erinaceus powder was found to increase fecal lipid levels in excreted matter. Further in vitro investigation showed that ethanol extract inhibited the activity of lipase, and four lipase-inhibitory compounds were isolated from the extract: hericenone C, hericenone D, hericenone F, and hericenone G. In short, we suggest that H. erinaceus has an anti-obesity effect during menopause because it decreases the ability to absorb lipids.
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Hericium erinaceus is an important mushroom with edible values and medicinal properties. Both the mycelium and the fruiting bodies contain many bioactive compounds with drug efficacy. Recent evidence demonstrates that it is helpful to various diseases, such as Alzheimer's disease, immunoregulatory, and many types of cancer. Furthermore, emerging pieces of evidence have shown that different active molecules in H. erinaceus have different functions on different organs in different diseases via the different mechanisms. Drawing on current research results, this review mainly focuses on the therapeutic effects of H. erinaceus on various diseases of multiple physiological systems, including the nervous system, digestive system, circulatory system, and immune system. This paper also discusses systematically the efficient protection of H. erinaceus against the diseases from the intricate experimental proofs by using the systematic viewpoints, which provides a framework for future research directions.
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Total syntheses of 5'- and 7'-oxidized geranyl resorcylates isolated from the fruiting bodies of Hericium erinaceum and the submerged cultures of a Stereum species were achieved. Our synthesis features derivatization of a suitably functionalized 5'-oxidized geranyl phthalide as a common intermediate, which was obtained by Stille coupling between the phthalide core and the side chain, into a series of natural products by divergent functional group manipulations. The crucial C5'-oxygen functionality was installed at the initial stage by alkylation by an alpha-cyano ethoxyethyl ether. From a common synthetic intermediate, eight total syntheses including hericenones A, B, and I, hericenols B, C and D, and erinacerins A and B were achieved (hericenol B and erinacerin B were synthesized as racemates). The structure of hericenone B established in the isolation paper was unambiguously revised as the carbonyl regioisomer at the lactam moiety.
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Novel cytotoxic phenols, hericenone A () and B () were isolated from the mushroom . These structures were determined by interpretation of spectral data and chemical analyses.
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The structures of novel diterpenoids, erinacines A, B, and C, isolated from the cultured mycelia of Hericium erinaceum were determined by interpretation of the spectral data, and chemical and enzymatic reactions. These compounds showed potent stimulating activity of nerve growth factor (NGF)-synthesis.
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Novel compounds, hericenones C (3), D (4) and (5) were isolated from the mushroom Hericium erinaceum. These structures were determined by interpretation of the spectral data, and chemical and enzymatic reactions. These compounds have stimulating activity of the synthesis of nerve growth factor (NGF).
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Novel chromans, hericenones F, G and H were isolated from the mushroom Hericium erinaceum. These compounds stimulated the synthesis of nerve growth factor (NGF) in vitro.
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Nerve growth factor (NGF) is an essential protein for supporting growth and maintenance of peripheral sympathetic neurons. A novel diterpenoid erinacine, isolated from the cultured mycelia of Hericium erinacium, is known to have a potent stimulating effect on NGF synthesis. The effects of erinacine and related compounds in the brain in vivo are not known. In this study, we examined the effects of erinacine A on the production of NGF and catecholamines which stimulate NGF synthesis in the brain of rats. Rats were treated with erinacine A by intubation for the first 3 weeks from birth to weaning and intragastrically from weeks 4 to 5. Rats treated with this compound had increased levels of both noradrenaline and homovanillic acid in the locus coeruleus (LC) at 4 weeks of age and increased levels of NGF in both LC and hippocampus at 5 weeks of age. The effects of erinacine A were confirmed in the central nervous system in rats.
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The structures of erinacines E, F and G from mycelia of Hericium erinaceum were determined by spectroscopic and/or X-ray analysis. Erinacines E and F exhibited potent stimulating activity against NGF synthesis by astroglial cells.
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We investigated antitumor effects of the following four extracts of freeze-dried Hericium erinaceus mushrooms in Balb/c mice intracutaneously transplanted on the backs with CT-26 colon cancer cells: HWE, hot water extraction by boiling in water for 3 h; MWE, microwaving in 50% ethanol/water at 60 W for 3 min; and ACE and AKE, boiling in 1% HCl or 3% NaOH for 2 h. HWE and MWE with a higher content of β-glucans, determined by an assay kit, than ACE and MKE were active in all bioassays. Gas chromatography/mass spectrometry analyses showed the presence of 40, 27, 16, and 13 compounds, respectively, in the four extracts. Daily intraperitoneal (ip) injections of HWE and MWE for 2 weeks significantly reduced tumor weights by 38 and 41%. Tumor regressions were associated with changes in the following cancer biomarkers as compared to phosphate buffer (PBS)-treated control mice: 2.7- and 2.4-fold increases in cytolytic activity of splenic natural killer (NK) cells; restored nitric oxide production and phagocytosis in peritoneal macrophages to 95-98% of normal levels; ∼2-fold increase in released pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 from macrophages; and ∼56 and ∼60% reductions in the number of blood vessels inside the tumor. The pro-angiogenic factors vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2), and 5-lipoxygenase (5-LOX) were also significantly reduced in mRNA and protein expression by tumor genes. Enzyme-linked immunosorbent assay of tumor cells confirmed reduced expression of COX-2 and 5-LOX (32 and 31%). Reduced COX-2 and 5-LOX expression down-regulated VEGF expression, resulting in inhibition of neo-angiogenesis inside the tumors. The results indicate that induction of NK activity, activation of macrophages, and inhibition of angiogenesis all contribute to the mechanism of reduction of tumor size.
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The visual retention test to be described here was developed as a practical means of fulfilling what I have long felt to be a need in the usual clinical examination of patients, namely, a short test to supplement the auditory-vocal digit span test in the investigation of immediate memory.The auditory-vocal digit span test, devised in 1887 by Jacobs,1 has become a stable feature of most clinical examination schemes. It measures retention or immediate memory, which is justifiably considered to be a significant aspect of mental capacity and one which is especially important clinically because of its close relationship to mental impairment. The test has obvious technical advantages, such as brevity of administration, lack of need for test materials and the objective character of the patient's performance.Nevertheless, while it is a useful single test, both clinical experience and experimental observations indicate that it cannot be considered to be
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Hericium erinaceus, a well known edible mushroom, has numerous biological activities. Especially hericenones and erinacines isolated from its fruiting body stimulate nerve growth factor (NGF) synthesis, which expects H. erinaceus to have some effects on brain functions and autonomic nervous system. Herein, we investigated the clinical effects of H. erinaceus on menopause, depression, sleep quality and indefinite complaints, using the Kupperman Menopausal Index (KMI), the Center for Epidemiologic Studies Depression Scale (CES-D), the Pittsburgh Sleep Quality Index (PSQI), and the Indefinite Complaints Index (ICI). Thirty females were randomly assigned to either the H. erinaceus (HE) group or the placebo group and took HE cookies or placebo cookies for 4 weeks. Each of the CES-D and the ICI score after the HE intake was significantly lower than that before. In two terms of the ICI, "insentive" and "palpitatio", each of the mean score of the HE group was significantly lower than the placebo group. "Concentration", "irritating" and "anxious" tended to be lower than the placebo group. Our results show that HE intake has the possibility to reduce depression and anxiety and these results suggest a different mechanism from NGF-enhancing action of H. erinaceus.
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Platelet aggregation in the blood vessel causes thrombosis. Therefore, inhibitors of platelet aggregation promise to be preventive or therapeutic agents of various vascular diseases, including myocardial infarction and stroke. In the present study, we found that hericenone B had a strong anti-platelet activity and it might be a novel compound for antithrombotic therapy possessing a novel mechanism. Prior to this study, we examined anti-platelet aggregation activity of ethanol extracts of several species of mushrooms, and found that extract of Hericium erinaceus potently inhibited platelet aggregation induced by collagen. Therefore, we first fractionated the ethanol extract of H. erinaceus to identify the active substances. The anti-platelet activity of each fraction was determined using washed rabbit platelets. As a result, an active component was isolated and identified as hericenone B. Hericenone B selectively inhibited collagen-induced platelet aggregation, but it did not suppress the aggregation induced by U46619 (TXA₂ analogue), ADP, thrombin, or adrenaline. Furthermore, hericenone B did not inhibit arachidonic acid- or convulxin (GPVI agonist)-induced platelet aggregation. Therefore, hericenone B was considered to block collagen signaling from integrin α2/β1 to arachidonic acid release. Moreover, we found that collagen-induced aggregation was inhibited by hericenone B in human platelets, similar to in rabbit platelets.
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Compare diagnostic characteristics of brief cognitive screening tests in residential care/assisted living (RC/AL) residents. Cross-sectional study involving a comprehensive clinical examination to ascertain a consensus diagnosis of probable dementia, no significant cognitive impairment, or mild cognitive impairment (MCI), including both amnestic and non-amnestic subtypes. Fourteen RC/AL facilities in North Carolina. Participants were 146 RC/AL residents, aged 65 years or older, who did not have diagnosed cognitive impairment. Diagnostic characteristics of the Mini-Cog, the Mini-Mental State Exam (MMSE), and a new 50-point test based on expanding selected MMSE items (MMX). Overall, 55/146 (38%) participants were diagnosed with probable dementia, and 76 (52%) met criteria for MCI (most non-amnestic). Both the Mini-Cog and the MMSE showed high sensitivity and negative predictive value for dementia, but had relatively low sensitivity and negative predictive value for MCI. The Mini-Cog had low specificity and was less accurate as a dementia screen than either the MMSE or MMX. Reliability and validity data for the MMX were satisfactory, and it performed better as a screening test for MCI than either the MMSE or Mini-Cog. Although the MMSE and Mini-Cog are both sensitive to dementia, modest specificity and positive predictive value may limit their utility as screening tools. Preliminary MMX data suggest it improves screening for MCI compared to the Mini-Cog or MMSE, while providing a similar level of screening for dementia. Further work is needed to identify suitable instruments for cognitive screening across the range of MCI and dementia.
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Neurotrophic factors are essential to maintain and organize neurons functionally; thereby neurotrophic factor-like substances or their inducers are expected to be applied to the treatment of neurodegenerative diseases such as Alzheimer's disease. In the present study, we firstly examined the effects of ethanol extracts of four edible mushrooms, Hericium erinaceus (Yamabushitake), Pleurotus eryngii (Eringi), Grifola frondosa (Maitake), and Agaricus blazei (Himematsutake), on nerve growth factor (NGF) gene expression in 1321N1 human astrocytoma cells. Among the four mushroom extracts, only H. erinaceus extract promoted NGF mRNA expression in a concentration-dependent manner. In addition, secretion of NGF protein from 1321N1 cells was enhanced by H. erinaceus extracts, and the conditioned medium of 1321N1 cells incubated with H. erinaceus extract enhanced the neurite outgrowth of PC12 cells. However, hericenones C, D and E, constituents of H. erinaceus, failed to promote NGF gene expression in 1321N1 cells. The enhancement of NGF gene expression by H. erinaceus extracts was inhibited by the c-jun N-terminal kinase (JNK) inhibitor SP600125. In addition, H. erinaceus extracts induced phosphorylation of JNK and its downstream substrate c-Jun, and increased c-fos expression, suggesting that H. erinaceus promotes NGF gene expression via JNK signaling. Furthermore we examined the efficacy of H. erinaceus in vivo. ddY mice given feed containing 5% H. erinaceus dry powder for 7 d showed an increase in the level of NGF mRNA expression in the hippocampus. In conclusion, H. erinaceus contains active compounds that stimulate NGF synthesis via activation of the JNK pathway; these compounds are not hericenones.
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A cut or crush injury to a peripheral nerve results in the degeneration of that portion of the axon isolated from the cell body. The rapid degeneration of this distal segment was for many years believed to be a process intrinsic to the nerve. It was believed that Schwann cells both phagocytosed degenerating axons and myelin sheaths and also provided growth factors to promote regeneration of the damaged axons. In recent years, it has become apparent that the degenerating distal segment is invaded by monocytes from the blood. We will review the evidence that these recruited macrophages play a role in both degeneration and regeneration of peripheral nerve axons after injury and consider whether the slow degeneration and poor monocyte recruitment in the central nervous system may contribute to the poor regeneration there.
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Macrophages are not only phagocytic cells but also secrete a plethora of growth factors that are potentially important for regeneration. This review will examine the emerging evidence of a likely contribution by macrophages to axonal regeneration.
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This review summarizes the current knowledge of characterized neurotrophic factors, including nerve growth factor (NGF) which serves as paradigmatic example when studying novel molecules. Special consideration is given to the function of neurotrophic factors in the adult and aging brain. Strategies are discussed for the eventual development of pharmacological applications of these molecules in the treatment of neurodegenerative diseases.
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Preclinical studies have demonstrated that nerve growth factor may prevent or reverse peripheral neuropathy. We have therefore tested the effects of recombinant human nerve growth factor in patients with diabetic polyneuropathy. A total of 250 patients with symptomatic diabetic polyneuropathy randomly received either placebo or one of two doses of recombinant human nerve growth factor for 6 months. Patients were assessed for symptoms and signs of polyneuropathy before and after treatment. Compared with placebo, recombinant human nerve growth factor led to significant improvement after 6 months of treatment, as measured by the sensory component of the neurologic examination, two quantitative sensory tests, and the impression of most subjects that their neuropathy had improved. Three prospectively identified multiple endpoint analyses indicated improvements in the nerve growth factor treatment groups over the placebo group in all three analyses (p = 0.032; p = 0.008; p = 0.005). Recombinant human nerve growth factor was well tolerated, with injection site discomfort reported as the most frequent adverse event. Recombinant human nerve growth factor appears to be safe and shows preliminary evidence of efficacy in patients with symptomatic diabetic polyneuropathy.
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Nerve growth factor is a neurotrophic factor that promotes the survival of small fiber sensory neurons and sympathetic neurons in the peripheral nervous system. Recombinant human nerve growth factor (rhNGF) has demonstrated efficacy as treatment for peripheral neuropathy in experimental models and phase 2 clinical trials. To evaluate the efficacy and safety of a 12-month regimen of rhNGF in patients with diabetic polyneuropathy. Randomized, double-blind, placebo-controlled phase 3 trial conducted from July 1997 through May 1999. Eighty-four outpatient centers throughout the United States. A total of 1019 men and women aged 18 to 74 years with either type 1 or type 2 diabetes and a sensory polyneuropathy attributable to diabetes. Patients were randomly assigned to receive either rhNGF, 0.1 microg/kg (n = 504), or placebo (n = 515) by subcutaneous injection 3 times per week for 48 weeks. Patients were assessed at baseline, 12 weeks, 24 weeks, and 48 weeks. The primary outcome measure was a change in neuropathy between baseline and week 48, demonstrated by the Neuropathy Impairment Score for the Lower Limbs, compared between the 2 groups. Secondary outcome measures included quantitative sensory tests using the CASE IV System, the Neuropathy Symptom and Change questionnaire, the Patient Benefit Questionnaire (PBQ), and a global symptom assessment, as well as nerve conduction studies and occurrence of new plantar foot ulcers. Patients also were evaluated for presence of adverse events. Among patients who received rhNGF, 418 (83%) completed the regimen compared with 461 (90%) who received placebo. Administration of rhNGF was safe, with few adverse events attributed to treatment apart from injection site pain/hyperalgesia and other pain syndromes. However, neither the primary end point (P =.25) nor most of the secondary end points demonstrated a significant benefit of rhNGF. Exceptions were the global symptom assessment (P =.03) and 2 of 32 comparisons within the PBQ, which showed a modest but significant benefit of rhNGF (P =.05 for severity of pain in the legs and P =.003 for 6-month symptoms in the feet and legs). Unlike previous phase 2 trials, this phase 3 clinical trial failed to demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy. JAMA. 2000;284:2215-2221.
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Novel diterpenoids, erinacines H (1) and I (3), were isolated from the cultured mycelia of Hericium erinaceum. The structures of the compounds were determined by interpretation of the spectral data. Erinacine H showed stimulating activity of nerve growth factor (NGF)-synthesis.
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Since their discovery in the 1950s, neurotrophic factors have raised expectations that their clinical application to neurodegenerative diseases might provide an effective therapy for what are now untreatable conditions. Nerve growth factor (NGF) was the first neurotrophic factor to be discovered and was one of the earliest to proceed to clinical trials. NGF, which is selectively trophic for small fiber sensory and sympathetic neurons, was selected as a potential theraphy for diabetic polyneuropathy becaus of the serious consequences associated with degeneration of those neuronal populations in this condition. In addition, evidence shows that reduced availability of NGF may contribute to the pathogenesis of diabetic neuropathy, and animal models of neuropathy respond to the exogenous administration of NGF. Two sets of phase II clinical trails suggested that recombinant human NGF (rhNGF) administration was effective at ameliorating the symptoms associated with both diabetic polyneuropathy and HIV-related neuropathy. These early studies, however, revealed that painful side effects were dose limiting for NGF. A large-scale phase III clinical trail of 1019 patients randomized to receive either rhNGF or palcebo for 48 weeks failed to confirm the earlier indications of efficacy. Among the explanations offered for the discrepancy between the two sets of trails was a robust palcebo effect, inadequate dosage, different study populatioms, and changes to the formulation of rhNGF for the phase III trail. As a result of the phase III outcome, Genentech has decided not to proceed with further development of rhNGF.
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HEP3, a beta-D-glucan slightly soluble in water, was isolated from the alkaline extract of the fruiting bodies of Hericium erinaceus. Its chemical structure was investigated by methylation analysis, periodate oxidation, Smith degradation and by IR and NMR spectroscopy. It was shown to have a main chain composed of beta-(1-->3)-linked D-glucopyranosyl residues, with single unit glucosyl branches attached to O-6 of every third backbone residue. Viscometry and Congo red reaction indicated that HEP3 has a highly ordered hydrogen-bond dependent conformation in aqueous solution, which collapses in strong alkaline solution.
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The Mini-Mental State Examination (MMSE) is commonly used as a screening tool to detect dementia. However, it performs poorly in identifying persons with mild neurocognitive disorder. The Saint Louis University Mental Status (SLUMS) examination is a 30-point screening questionnaire that tests for orientation, memory, attention, and executive functions. The objective of this study was to compare SLUMS and the MMSE for detecting dementia and mild neurocognitive disorder (MNCD) using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Patients at the Veterans' Affairs Geriatric Research, Education and Clinical Center, St. Louis, MO (N = 702) were clinically classified as having normal cognitive functioning, MNCD, or dementia based on DSM-IV criteria. The SLUMS and MMSE were administered for comparison. Mean age was 75.3 years (standard deviation: 5.5). Regarding education, 62.4% of the sample had at least completed high school and 30.6% had not. Sensitivity and specificity were calculated and receiver operator curves (ROCs) generated for SLUMS and MMSE as a function of diagnosis (MCND versus dementia) and education. Both the SLUMS and MMSE produced acceptable ROCs for the diagnosis of dementia, but the ROCs for SLUMS were better than the MMSE for the diagnosis of MNCD in both education groups. These results suggest that the SLUMS and MMSE have comparable sensitivities, specificities, and area under the curve in detecting dementia. Although the definition of MNCD is controversial, the authors believe that the SLUMS is possibly better at detecting mild neurocognitive disorder, which the MMSE failed to detect, but this needs to be further investigated.
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Little is known about how synaptic activity is modulated in the central nervous system. We have identified SCRAPPER, a synapse-localized E3 ubiquitin ligase, which regulates neural transmission. SCRAPPER directly binds and ubiquitinates RIM1, a modulator of presynaptic plasticity. In neurons from Scrapper-knockout (SCR-KO) mice, RIM1 had a longer half-life with significant reduction in ubiquitination, indicating that SCRAPPER is the predominant ubiquitin ligase that mediates RIM1 degradation. As anticipated in a RIM1 degradation defect mutant, SCR-KO mice displayed altered electrophysiological synaptic activity, i.e., increased frequency of miniature excitatory postsynaptic currents. This phenotype of SCR-KO mice was phenocopied by RIM1 overexpression and could be rescued by re-expression of SCRAPPER or knockdown of RIM1. The acute effects of proteasome inhibitors, such as upregulation of RIM1 and the release probability, were blocked by the impairment of SCRAPPER. Thus, SCRAPPER has an essential function in regulating proteasome-mediated degradation of RIM1 required for synaptic tuning.
Composition and mechanism of antitumor effects of Hericium erinaceus mushroom extracts in tumor-bearing mice
  • S P Kim
  • M Y Kang
  • J H Kim
  • Nam Sh
  • M Friedman
Kim SP, Kang MY, Kim JH, Nam SH and Friedman M (2011) Composition and mechanism of antitumor effects of Hericium erinaceus mushroom extracts in tumor-bearing mice. J Agric Food Chem 59, 9861-986.
A beta-D-glucan isolated from the fruiting bodies of Hericium erinaceus and its aqueous conformation
  • Q Dong
  • Jia Lm
  • J N Fang
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