Article

Inhibitory effect of hericenone B from Hericium erinaceus on collagen-induced platelet aggregation

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Abstract

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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... Platelet aggregation was determined by a standard turbidimetric method using an aggregometer (PAM-6C, Merbanix, Tokyo, Japan), as described previously [15,16]. Platelet aggregation was expressed as an increase in light transmission. ...
... Samples for observation by scanning electron microscopy were prepared as described previously [16]. Briefly, washed platelet aggregation was initiated by collagen stimulation for 3 min in the presence or absence of licochalcones, and then fixed overnight with 1% glutaraldehyde. ...
... It is well known that collagen causes platelet aggregation mediated through arachidonic acid release by PLA 2 at the inner plasma membrane of platelets, and COX inhibitors such as aspirin can block the platelet aggregation induced by collagen [16]. Therefore, we examined whether licochalcone A, which inhibited collagen-induced platelet aggregation at a lower concentration compared with the other licochalcones, also inhibits extrinsic arachidonic acid-induced platelet aggregation. ...
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Licochalcones extracted from Glycyrrhiza inflata are known to have a variety of biological properties such as anti-inflammatory, anti-bacterial, and anti-tumor activities, but their action on platelet aggregation has not yet been reported. Therefore, in this study we investigated the effects of licochalcones on platelet aggregation. Collagen and U46619, a thromboxane A2 receptor agonist, caused rabbit platelet aggregation, which was reversed by pretreatment with licochalcones A, C and D in concentration-dependent manners. Among these compounds, licochalcone A caused the most potent inhibitory effect on collagen-induced platelet aggregation. However, the licochalcones showed marginal inhibitory effects on thrombin or ADP-induced platelet aggregation. In addition to rabbit platelets, licochalcone A attenuated collagen-induced aggregation in human platelets. Because licochalcone A also inhibited arachidonic acid-induced platelet aggregation and production of thromboxane A2 induced by collagen in intact platelets, we further examined the direct interaction of licochalcone A with cyclooxygenase (COX)-1. As expected, licochalcone A caused an inhibitory effect on both COX-1 and COX-2 in vitro. Regarding the effect of licochalcone A on COX-1 enzyme reaction kinetics, although licochalcone A showed a stronger inhibition of prostaglandin E2 synthesis induced by lower concentrations of arachidonic acid, Vmax values in the presence or absence of licochalcone A were comparable, suggesting that it competes with arachidonic acid at the same binding site on COX-1. These results suggest that licochalcones inhibit collagen-induced platelet aggregation accompanied by inhibition of COX-1 activity.
... It has been shown in rabbits that adrenaline alone does not induce platelet aggregation, but that it potentiates platelet aggregation induced by other platelet agonists such as ADP, collagen, thrombin, thromboxane A2 and serotonin [25][26][27][28] . The α 2 -adrenoceptors have also been found on rabbit platelets [2] . ...
... The results of this study both confirmed and extended previous investigations which reported that although adrenaline alone did not induce a change in rabbit platelet aggregation, it potentiated platelet aggregation induced by other platelet agonists [25][26][27][28] . Furthermore, the results of this study revealed that noradrenaline potentiated the ADP-induced platelet aggregation in a dose- Each value indicates the mean ± SEM (n = 5). ...
Article
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Background/aims: Imidazoline α2-adrenergic agents exert complex effects on mammalian platelet aggregation. Although non-adrenergic, imidazoline (I) receptors have been revealed in human platelets, there is limited information about imidazoline's action on platelet aggregation. This study aimed to investigate aggregatory and anti-aggregatory effects of various imidazoline or non-imidazoline α-adrenergic agents on rabbit platelets. Methods: Aggregatory responses of agents on rabbit platelets were examined by turbidimetric method. Radioligand binding assay to platelet I1 and I2 receptors was performed using [(3)H]-clonidine and [(3)H]-idazoxan, respectively. Results: Aggregation was not induced by α-adrenoceptor agonists alone. Adrenaline and noradrenaline produced dose-dependent potentiation of ADP- or collagen-induced aggregation. Imidazoline adrenoceptor agonists clonidine and p-aminoclonidine also potentiated ADP-induced platelet aggregation. The α2-adrenoceptor antagonists and/or certain imidazoline adrenergic agents inhibited adrenaline-potentiated aggregation in a dose-dependent manner, whereas α1-adrenoceptor antagonists and non-imidazoline α-adrenergic agents were either ineffective or less effective in inhibiting adrenaline-potentiated aggregation. Rabbit platelets did not have I1 receptors, but had I2 receptors, indicating that adrenaline-potentiated platelet aggregation was inhibited by idazoxan, but not by imidazoline compounds clonidine and oxymetazoline. Conclusions/implications: These results demonstrated that α2-adrenoceptor-blocking agents and/or imidazoline α-adrenergic agents effectively inhibit adrenaline-potentiated platelet aggregation. It is proposed that imidazoline structure in part plays a role in the inhibition of adrenaline-potentiated aggregation.
... Mori et al. [20] found that the ethanol extract of H. erinaceus potently inhibited platelet aggregation induced by collagen. They identified hericenone B as the active compound against platelet aggregation in human and rabbit platelets. ...
... In addition, a mixture of palmitic and stearic acid, a mixture of behenic acid and tetracosanic acid and a mixture of 5-α-ergostan-3one, 5-α-stigmasten-22-en-3-one and 5-α-stigmastan-3-one were also been isolated by Qian et al. [38]. Hericenone B, a phenolic compound, was isolated from the ethanol extract of H. erinaceus and identified as the potential anti-platelet aggregating agent by Mori et al. [20]. ...
Article
Abstract Mushrooms are considered as nutritionally functional foods and source of physiologically beneficial medicines. Hericium erinaceus, also known as Lion's Mane Mushroom or Hedgehog Mushroom, is an edible fungus, which has a long history of usage in traditional Chinese medicine. This mushroom is rich in some physiologically important components, especially β-glucan polysaccharides, which are responsible for anti-cancer, immuno-modulating, hypolipidemic, antioxidant and neuro-protective activities of this mushroom. H. erinaceus has also been reported to have anti-microbial, anti-hypertensive, anti-diabetic, wound healing properties among other therapeutic potentials. This review article has overviewed the recent advances in the research and study on H. erinaceus and discussed the potential health beneficial activities of this mushroom, with the recognition of bioactive compounds responsible for these medicinal properties.
... Although numerous compounds and secondary metabolites were detected in extracts derived from fungi (ascomycetes and basidiomycetes) and were reported to exhibit anti-platelet effects against platelet agonists, including anti-PAF activities and reduction of PAF-synthesis, [10][11][12][13][14][15][16][17][18][19][20][21], yet there is still a lack of pertinent studies attributing similar beneficial bioactivities to the lipid constituents of Beauveria species. ...
... Bioactive secondary metabolites of fungi, such as those derived from the genera Aspergillus, Penicillium, and Talaromyces fungal groups, have proven to be rich resources of compounds with medicinal and/or agricultural applications [35]. Several bioactive compounds from various fungal species have been found to exhibit potent anti-PAF effects, as well as to inhibit PAF-synthesis, but these are mostly different from the polar lipids obtained from B. bassiana extracts in this work [12][13][14][15][16][17][18][19][20][21]36,37]. ...
Article
In the present work the entomopathogenic fungus B. bassiana lipids were studied against the potent pro-inflammatory and thrombotic mediators implicated in several disorders, platelet-activating factor (PAF) and thrombin. Bioactivities of lipid extracts from B. bassiana cells and culture supernatants and of their lipid fractions separated by a one-step HPLC-analysis ere assessed against the PAF/Thrombin-induced aggregation of washed rabbit platelets. Lipid extracts from both cell-biomass and supernatant inhibited strongly PAF/Thrombin-activities and platelet-aggregation, exhibiting higher specificity against PAF. Similarly, HPLC-derived lipid-fractions of phenolics/glycolipids, Sphingomyelins and Phosphatidylcholines (PC) showed strong anti-PAF potency. PC PAF-like molecules exhibited the strongest antagonistic anti-PAF effects, while in higher amounts they agonistically inhibited PAF-activities. Some bioactive lipids with strong anti-PAF effects are exo-cellularly secreted in the culture media during fungal growth, while others are not. The presence of such lipid bioactives in B. bassiana with strong anti-inflammatory and anti-thrombotic properties, provide new perspectives and putative future applications for this entomopathogenic fungus.
... Erinacines are able topromote the synthesis of nerve growth factors, thus have neuroprotective properties [35,36]. Phenolics compounds, as well as terpenoid lactones such as hericenone C, hericenone D, hericenone E, and hericenone H,can also promote the synthesis of nerve growth factors [37][38][39]. The anticancer properties of some of these compounds are also mentioned [40]. ...
... Erinacines are able topromote the synthesis of nerve growth factors, thus have neuroprotective properties [35,36]. Phenolics compounds, as well as terpenoid lactones such as hericenone C, hericenone D, hericenone E, and hericenone H, can also promote the synthesis of nerve growth factors [37][38][39]. The anticancer properties of some of these compounds are also mentioned [40]. ...
Article
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Natural cosmetics are becoming more and more popular every day. For this reason, this work investigates the properties of mushroom extracts, which are not as widely used in the cosmetics industry as plant ingredients. Water extracts of Grifolafrondosa (Maitake), Hericiumerinaceus (Lion’s Mane) and Ganoderma lucidum (Reishi) were tested for their antioxidant properties, bioactive substances content, skin cell toxicity, ability to limit TEWL, effect on skin hydration and pH, and skin irritation. Our research showed that Maitake extract contained the highest amount of flavonoids and phenols, and also showed the most effective scavenging of DPPH and ABTS radicals as well as Chelation of Fe2+and FRAP radicals, which were 39.84% and 82.12% in a concentration of 1000 µg/mL, respectively. All tested extracts did not increase the amount of ROS in fibroblasts and keratinocytes. The addition of mushroom extracts to washing gels reduced the irritating effect on skin, and reduced the intracellular production of free radicals, compared with the cosmetic base. Moreover, it was shown that the analyzedcosmetics had a positive effect on the pH and hydration of the skin, and reduced TEWL.
... In a different research, Mori et al. (2010) isolated the aromatic compound hericenone B from H. erinaceus, which proved to have antiplatelet properties. Hericenone B was able to inhibit collagen-induced platelet aggregation in rabbit and human platelets, but not aggregation stimulated by U46619, ADP, thrombin, or adrenaline. ...
... Further investigation was carried out to examine the possibility that hericenone B may inhibit aggregation due to arachidonic acid synthesis of TXA 2 and GPVI (using convulxin, a GPVI agonist). However, hericenone B did not inhibit aggregation induced by arachidonic acid and convulxin, suggesting that hericenone B may inhibit platelet aggregation through a mechanism upstream of arachidonic acid metabolism (Mori et al., 2010). ...
Article
Atherosclerosis is a complex pathology that involves several factors in its development, like oxidative stress, inflammation, hyperlipidemia, platelet aggregation and thrombus formation. Several drugs and therapeutic approaches have been developed to handle these aspects of atherosclerosis. However, some of these treatments can be costly and have undesirable side effects. Many constituents of mushrooms have been shown to have potential anti-atherosclerotic effects in several in vitro and in vivo studies. Recently, the possible mechanisms in which they exert these effects have also been elucidated. In this review, some of the research focusing on mushrooms and their potential anti-atherosclerotic effects are examined. Many mushroom species exhibited anti-oxidative, anti-inflammatory and hypolipidemic effects that can potentially attenuate the progression of atherosclerosis, either through their isolated compounds or use of crude extracts. More studies are focused on the effect that mushrooms have on gene expressions that are involved in oxidative stress, inflammation, and hyperlipidemia. These studies could provide us with a better understanding on the mechanisms in which the consumption of mushrooms could exert their possible anti-atherosclerotic effects. Further research needs to be done to uncover other possible mechanisms that are affected by mushroom use.
... Although some authors have demonstrated the presence of some macro-and microelements in H. erinaceus (Heleno et al., 2015), there has been no report about the effect of different growing media on the macro-and micro element content. Furthermore, many polysaccarides were isolated and identified by Mori et al. (2010) and Kim et al. (2011) from the fruitbody or mycelium of H. erinaceus. However, little is known about the antioxidant properties and total phenolic content (Wong et al., 2009;Han et al., 2013;Heleno et al., 2015;Koutrotsios et al., 2016)· For the above reasons, the objectives of this work were: (1) to determine suitable additive materials for the cultivation of H. erinaceus isolates; ...
Article
Four isolates of Hericium erinaceus cultivated in different growing media were investigated for their mycelial growth, yield, biological efficiency (BE), macro and micro element content, total phenolic content and antioxidant activity. In the study, oak sawdust (OS) was used as a base substrate, and cottonseed hulls (CSH) and olive press cake (OPC) were added at the ratios of 9:1, 8:2 and 7:3 to prepare the growing media. The control medium was prepared using OS and wheat bran (WB) at the rate of 8:2. The spawn run-period was shorter in all H. erinaceus isolates growing in the OS:WB (control) medium. The yield and BE (%) of H. erinaceus isolates ranged between 76.7 and 152.9 g/kg and 22.3–44.4%, respectively, depending on the growing medium used. The highest yield and BE% for all H. erinaceus isolates, except He-Trabzon, was obtained on 7OS:3CSH medium. The nutritional composition of H. erinaceus isolates varied with the growing medium, but there was no direct relationship between the macro- and micro-element content of the growing media and the nutrient content of the fruitbodies. The antioxidant activity and phenolic content of H. erinaceus isolates grown on different growing media ranged between 1.76 and 4.92 μmol TE/g fw and 0.318–0.663 mg GAE/g fw, respectively. The antioxidant activity and phenolic content of He- Ankara, He-Denizli and He-Trabzon were not affected by the growing media, whereas the addition of OPC to the oak sawdust substrate had a noticeable effect on the phenolic content and antioxidant activity of the fruitbodies of HE-İzmit. According to the results, cotton seed hulls and olive pess cake can be recommended as alternative additive materials to wheat bran to increase the yield of H. erinaceus. Finally, the use of olive press cake as substrate incrases the phenolic content of H. erinaceus mushrooms.
... 16 Hericenones A and B (cytotoxic phenols) 17 and a novel fatty acid 18,19 isolated from fruit bodies, as well as erinapyrones A and B (γ-pyrones), 20 hericenes A, B, and C (phenolic derivatives), 21 and erinapyrone C (γ-dihydropyrone) 21 isolated from mycelium, exhibited cytotoxicity against HeLa cells. Mori et al. 22 found that hericenone B had strong antiplatelet activity, and it might be a novel compound for antithrombotic therapy possessing a novel mechanism. Hericenone B has been shown to specifically inhibit collagen-induced platelet aggregation through the inhibition of upstream of arachidonic acid liberation in integrin α2/β1 signaling. ...
Article
We present a model case study of the activity of aqueous extract of Hericium erinaceus fresh fruit bodies in promoting functional recovery following crush injury to the peroneal nerve in adult female Sprague-Dawley rats. The aim was to explore the possible use of this mushroom in nerve repair. The activities of aqueous extract were compared to activities exhibited by mecobalamin (vitamin B12), which has been widely used in the treatment of peripheral nerve disorders. Analysis of walking track indicated that return of hind limb function and normal toe spreading occurred earlier in treated groups than in the negative control (non-treated) group. Regeneration of axons and reinnervation of motor endplates/neuromuscular junction in extensor digitorum longus muscle of rats in treated groups developed better than in the negative control group. Further, immunofluorescence studies also showed that dorsal root ganglia neurons ipsilateral to the crush injury in rats of treated groups expressed higher immunoreactivities for Akt and MAPK signaling pathways as well as c-Jun and c-Fos genes compared to the negative control group. Akt cascade plays a major role in mediating neurotrophin-promoted cell survival, while MAPK cascade is involved in mediating neurite outgrowth. Immediate early gene expression was also involved in the cascade of events leading to regeneration. Local axonal protein synthetic machinery was also enhanced in the distal segments of crushed nerves in treated groups. Therefore, daily oral administration of H. erinaceus could promote the regeneration of injured rat peroneal nerve in the early stage of recovery.
... In 2004, a methanol extract of Pleurotus florida Eger (an edible and commercially grown mushroom) was demonstrated to almost abolish ADP-induced platelet aggregation (95% reduction) after a 5 min incubation in washed-human platelets [77]. On the other hand, a dry extract of Stereum hirsutum demonstrated to partly diminish platelet activation by blocking thrombin active site (Fig. 2) [78] and an extract from Hericium erinaceus (i.e., hericenone B) to selectively impede collagen signaling from GPIIb/Ia [79]. Additionally, recent studies by Kamruzzaman and colleagues have provided detailed insights as to the mechanisms by which certain medicinal mushrooms may provide antiplatelet protection. ...
... 18 Hericenone B was also a promising preventive or therapeutic agent of thrombosis and vascular diseases as it potently inhibited platelet aggregation induced by collagen. 22 Hericenones C-E have been reported to be effective stimulators of NGF synthesis. 16 There was, however, no report on the biological activity of erinacerin A. Further, isohericerin, which is an isoindolinone alkaloid was reported to be cytotoxic to various cancer cell lines . ...
Article
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Hericium erinaceus (Bull.: Fr.) Pers. is an edible and medicinal mushroom used traditionally to improve memory. In this study, we investigated the neuritogenic effects of hericenones isolated from H. erinaceus and the mechanisms of action involved. H.erinaceus was cultivated and the secondary metabolites were elucidated by high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR). The secondary metabolites were tested for neurite outgrowth activity (if any). Rat pheochromocytoma cell (PC12) cells were employed and the nerve growth factor (NGF) level was also determined. The signaling pathways involved in the mushroom-induced neuritogenesis were investigated by using several pharmacological inhibitors. Hericenones B-E (1-4), erinacerin A (5) and isohericerin (6) were isolated from the basidiocarps of H. erinaceus. The hericenones did not promote neurite outgrowth but when induced with a low concentration of NGF (5 ng/mL), the neuritogenic activity was comparable to that of the positive control (50 ng/mL of NGF). Hericenone E was able to stimulate NGF secretion which was two-fold higher than that of the positive control. The neuritogenesis process was partially blocked by the tyrosine kinase receptor (Trk) inhibitor, K252a; suggesting that the neuritogenic effects was not solely due to NGF. Hericenone E also increased the phosphorylation of extracellular-signal regulated kinases (ERKs) and protein kinase B (Akt). Taken together, this study suggests that hericenone E potentiated NGF-induced neuritogenesis in PC12 cells via MEK/ERK and PI3K/Akt pathways.
... Hericenone B showed stimulating activity on release arachidonic acid, which mediated receptor thrombosis via collagen through α2/β1 in a tested rabbit. Specifically, only hericenone B showed inhibition of collagen-induced platelet aggregation when compared with hericenone C, D and E with inhibition at 30 μM, similar to 5 μM of aspirin as a reference investigated in vivo (Farndale et al. 2004;Mori et al. 2010). ...
Article
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DOI 10.1007/s11557-015-1105-4. Online Medicinal mushrooms have become a compelling topic because the bioactive compounds they contain promise a plethora of therapeutic properties. Hericium erinaceus commonly known as “Houtou” or “Shishigashira” in China and “Yamabushitake” in Japan, has commonly been prescribed in Traditional Chinese Medicine (TCM), because its consumption has been shown to be beneficial to human health. The species is found throughout the northern hemisphere in Europe, Asia, and North America. Hericium erinaceus has been firmly established as an important medicinal mushroom and its numerous bioactive compounds have been developed into food supplements and alternative medicines. However, the correspondence of the active components that cause the observed effects is often not clear. The mushroom as well as the fermented mycelia have been reported to produce several classes of bioactive molecules, including polysaccharides, proteins, lectins, phenols, and terpenoids. Most interestingly, two classes of terpenoid compounds, hericenones and erinacines, from fruiting bodies and cultured mycelia, respectively, have been found to stimulate nerve growth factor (NGF) synthesis. In this review we examine the scientific literature to explore and highlight the scientific facts concerning medicinal properties of H. erinaceus. We provide up-to-date information on this mushroom, including its taxonomy and a summary of bioactive compounds that appear related to the therapeutic potential of H. erinaceus. See http://link.springer.com/article/10.1007/s11557-015-1105-4
... Hot water extracts and ethanolic extracts reduced colon tumor weights in mice (Kim, Kang, Kim, Nam, & Friedman, 2011). Some active novel compounds isolated from methanolic extracts, i.e. hericerin and hericenones, protected against neurodegenerative diseases (Mori et al., 2008) and presented antithrombotic effects (Mori et al., 2010). ...
Article
Hericium erinaceus was processed to obtain soluble fractions using a sequence of stages consisting on: microwave hydrogravity (400 W), supercritical CO2 extraction (20 MPa, 40 °C, 10% ethanol) and the remaining raffinates were subjected either to enzyme assisted extraction (3% protease + cellulase + pectinase, 50 °C, 3 h) or to non-isothermal autohydrolysis with water (200 °C). More than 40% of the mushroom could be solubilized with the proposed green processes, which provided extracts containing the phenolic and the polysaccharide fractions. The phenolic components could be further concentrated by adsorption onto polymeric resins and desorption with 96% ethanol to yield concentrates with ABTS radical scavenging capacity equivalent to 0.6 g of Trolox/g extract.
... Obrázek 1: Korálovec ježatý (Hericum erinaceus) Foto: © Václav Burle a desítka hericenonù, ale stále jsou v houbì objevovány další (Lee et al., 2000;Kenmoku et al., 2002) a èasem se skupina tìchto látek rozšíøí o ty, které byly pøipraveny v laboratoøi (Watanabe a Nakada, 2008;Nakada, 2014). Chemická struktura nìkterých pøírodních erinacinù a hericenonù je uvedena na Obrázku 2. Erinaciny a hericenony jsou známé pøedevším jako stimulátory nervových rùstových faktorù (NGF); Ma et al. (2010), ale mají i další zajímavé farmakologické úèinky (Saito et al., 1998;Mori et al., 2010). ...
Article
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SOUHRN Houby jsou považovány za funkèní potraviny a zdroj fyziologicky prospìšných látek. Nedávné výzkumy ukázaly, že jedlé houby mohou hrát dùležitou roli v prevenci mnoha neurologických poruch spojených se stáøím, vèetnì Alzheimerovy a Parkinsonovy choroby. Herici-um erinaceus je jedlá houba, která má dlouhou historii použití v tradièní èínské medicínì. Tato houba je bohatá na nìkteré fyziologicky významné složky, zejména beta-glukanové polysacharidy, které jsou odpovìdné za protirakovinné, imunomodulaèní, hypolipidemické, antioxidaèní a neuroprotektivní úèinky houby. Tento pøehledový èlánek shrnuje nedávné pokroky ve výzkumu H. erinaceus, diskutuje o možné prospìšnosti této houby a poukazuje na bioaktivní látky zodpovìdné za její léèivé vlastnosti. SUMMARY Mushrooms are considered as nutritionally functional foods and source of physiologically beneficial medicines. Recent evidence demonstrates that edible mushrooms may play an important role in the prevention of many age-associated neurological dysfunctions, including Alzheimer's and Parkinson's diseases. Hericium erinaceus is an edible fungus, which has a long history of usage in traditional Chinese medicine. This mushroom is rich in some physiologically important components, especially beta-glucan polysaccharides, which are responsible for anti-cancer, immuno-modulating, hypolipidemic, antioxidant and neuro-protective activities of this mushroom. This review article has summarized recent advances in the research and study on H. erinaceus and discussed the potential health beneficial effects of this mushroom with the recognition of bioactive compounds responsible for these medicinal properties.
... HE has also been reported to be effective in improving mild cognitive impairment (16). In addition, hericenone B, one of hericenones isolated from the fruiting body of HE, was found to inhibit collagen-induced platelet aggregation, which is responsible for thrombosis leading to vascular dementia (17). Therefore, HE may be useful in producing a supplement for the treatment and prevention of dementia. ...
Article
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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.
... Différents métabolites ont été retrouvés en fonction des parties étudiées du champignon [xylane + [246] antitumoral [246], immunostimulateur [247] glucoxylane + [246] antitumoral [246], immunostimulateur [247] mannoglucoxylane + [246] antitumoral [246], immunostimulateur [247] galactoxyloglucane + [246] antitumoral [246], immunostimulateur [247] HEP3 (β-D-glucane) + [248] AUTRES COMPOSES erinacine A +[249];[250] stimulateur de la synthèse de NGF [249];[250] erinacine B + [249] stimulateur de la synthèse de [255], antidiabétique [254] erinacerine H + [256] + [254] antidiabétique [254] erinacerine I + [256] + [254] stimulateur de la synthèse de NGF [256], antidiabétique [254] erinacerine J + [257] + [254] antidiabétique [254] erinacerine K + [257] + [254] antidiabétique [254], antibactérien [257] erinacerine L + [254] antidiabétique [254] hercerine + [258] antitumoral [258] isohericine + [252];[259] antidiabétique [259] N-De phenylethyl isohericerin [258] antitumoral [258], inhibiteur de l'agrégation plaquettaire [260] hericenone C + [252];[258]; [261] stimulateur de la synthèse du NGF [41];[258];[261] hericenone D + [252];[258]; [261] stimulateur de la synthèse du NGF [41];[258];[261] hericenone E + [252];[258]; [261] potentialise la neuritogenèse induite [252], stimulateur de la synthèse du NGF [41];[258];[261] hericenone F + [258] stimulateur de la synthèse de NGF [258] hericenone G + [258] stimulateur de la synthèse de NGF [258] hericenone H + [258] stimulateur de la synthèse de NGF [41];[258] hericenone I + [262] hericenone J + [262];[263] isohericenone J + [263] isoericerine + [263] antitumoral [263] hericerine + [263] héricérine A + [263] antitumoral [263] HEG-5 (glycoprotéine) ...
Research
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Cultivation of macrofungi used in food supplements Les champignons sont traditionnellement utilisés dans le domaine de la santé, en particulier en Asie, et leur consommation dans les compléments alimentaires par la population Française va croissante. Sont présentées dans cette thèse les principales méthodes de culture des macromycètes et leurs compositions en métabolites selon les types de culture de certains d’entre eux que sont Hericium erinaceus, Lentinula edodes, Pleurotus ostreatus, Ganoderma lucidum et Grifola frondosa. Il existe très peu de données comparatives entre les composés issus des différents modes de culture des champignons, il apparait donc difficile de comparer entre eux deux compléments alimentaires issus de deux modes de production différents, en terme de composition chimique et donc d’efficacité. Mot-clés : - Hericium erinaceus - Lentinula edodes - Pleurotus ostreatus - Ganoderma lucidum - Grifola frondosa - complément alimentaire - culture - métabolite fongique Keywords: - Grifola frondosa - dietary supplement - cultivation - fungal metabolite - Hericium erinaceus - Lentinula edodes - Pleurotus ostreatus - Ganoderma lucidum
... Antiplatelet therapy is an efficient prevention method of thrombosis and similarly for the treatment and prevention of various cardiovascular diseases (Mori et al. 2010). Mushroom substances demonstrate inhibitory activity on platelet aggregation. ...
... Hericenone B (Fig. 6f) obtained from lion's mane mushroom is capable of inhibiting blood platelet aggregation [139]. Hericium erinaceum may regulate functions of the nervous, digestive, circulatory and immune systems of the organism, which would promote overall human health [140]. ...
Article
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Hericium erinaceum (Bull.: Fr.) Pers. is an edible fungus of great significance in medicine. It is rarely found in Europe, in contrast, it is common in Japan and North America. Its fruitbodies have been well-known for hundreds of years in traditional Chinese medicine and cuisine. A cradle of H. erinaceum cultivation is Asia. In Eastern Europe is rare in natural habitats, but can be successfully cultivated. Both fruitbodies and mycelia are rich in active, health promoting substances. Tests of substances extracted from this mushroom carried out on animals and in vitro have given good results. They can be used in the treatment of cancer, hepatic disorders, Alzheimer’s and Parkinson’s diseases, wound healing. They improve cognitive abilities, support the nervous and immune systems. Promising results have been reported in clinical trials and case reports about the human treatment (e.g., recovery from schizophrenia, an improvement of the quality of sleep, alleviation of the menopause symptoms). The subject of this paper is to summarize information about the development of mycelium, the best conditions for cultivation of fruitbodies, bioactive substances and their use in medicine.
... W badaniach in vitro związek ten selektywnie hamował agregację płytek krwi indukowaną kolagenem, nie upośledzał jednak agregacji indukowanej analogiem tromboksanu A 2 (TXA 2 ), ADP, trombiną lub adrenaliną oraz nie powodował zahamowania agregacji płytek indukowanej kwasem arachidonowym lub konwulksyną. Aktywność hericenonu B wynika prawdopodobnie z obecności w jego cząsteczce charakterystycznego ugrupowania γ-laktamowego oraz podstawnika przy atomie azotu [48,[54][55][56][57][58]. str. ...
Thesis
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Lion’s Mane Mushroom (Hericium erinaceum) is an edible mushroom that contains compounds possessing a strong stimulating effect on nerve growth factor (NGF) synthesis as well as immunostimulating, cytotoxic and antibacterial activity. The aim of the thesis was to isolate low-molecular weight metabolites from a liquid culture of H. erinaceum, to develop and validate methods for their quantitative determination, and to optimize the culture medium composition ensuring their effective biosynthesis. Of the isolated compounds, four (i.e. ergosterol peroxide, erinacine A, erinacine E and ergosterol) were obtained from the mycelium, whereas one of them (4-chloro-3,5- dimethoxytoluene) was extracted from the culture medium. It was found that erinacines A and E, ergosterol peroxide and chlorinated orcinol derivative exhibit a weak, dose-dependent ability to DPPH free radical scavenging. The analysis of cytotoxicity of erinacines A and E showed that these compounds are inactive against human cervical carcinoma (HeLa) cells and human leukemia K562 cells. Furthermore, erinacine A exhibited antimicrobial activity against some Gram-positive bacteria. The developed densitometric methods of 4-chloro-3,5-dimethoxytoluene, ergosterol peroxide and ergosterol quantitative determination and the HPLC assay of erinacine A were found to be highly specific, reproducible, precise and accurate. The new densitometric method of ergosterol peroxide analysis was applied for its quantitative determination in mycelia and fruiting bodies of several mushroom species (Laetiporus sulfureus, Morchella esculenta, Boletus edulis, B. badius, and Suillus bovinus). On the basis of these findings together with the results from a two-dimensional TLC experiment it was found that ergosterol peroxide is not an artifact (as it was regarded) but a common fungal secondary metabolite. The culture medium composition was optimized by a “one-factor-at-a-time method”, the orthogonal matrix L9 (3^4) method and the central composite rotatable design 2^4 combined with response surface methodology. The effect of different carbon and nitrogen sources, initial pH, vitamins, mineral elements, elicitors, growth stimulators and toluene (which increases cell membrane permeability) was examined. It was established that the most favorable combination of nutrient medium constituents ensuring the highest erinacine A production is: glucose 69.9 g/l, casein peptone 11.2 g/l, NaCl 1.45 g/l, ZnSO4·7H2O 55.2 mg/l, KH2PO4 1.0 g/l; pH 4.5. The fermentation kinetics in a bioreactor under optimal conditions showed that the production of erinacine A and 4-chloro-3,5-dimethoxytoluene proceeded most effectively during the exponential growth phase, reaching a maximum value on day 8. It was also found that the biosynthesis of ergosterol peroxide is highly correlated with mycelial growth and is not connected with the concentration of ergosterol but only with the physiological state of mush- room cells. An extensive production of erinacine A proceeded up to the beginning of the stationary phase and then declined rapidly according to first order reaction kinetics. The optimization of nutrient medium composition resulted in 160 times higher erinacine A production (192 mg/l) compared with its yield from the basic nutrient medium. Moreover, the concentration of erinacine A in the obtained mycelium was 844 times greater than in the naturally grown fruiting body of H. erinaceum (32.1 µg/l).
... More than 30 congeners have been isolated so far and their biological activities are extensively investigated. 1,2 Due to their exceptional structural diversity and broad biological activities including antitumor, 15,16 inhibition of platelet aggregation, 17 antioxidant activity, 18 α-glucosidase inhibition, 19,20 neuritogenesis, 21 and neuroprotection, 22 we elected to pursue the collective total synthesis of hericenones C−H and explore the structure−activity relationships (SAR) of their derivatives. 23−26 Structurally, the geranyl-resorcinols isolated from H. erinaceus can be classified into four groups, from Type 1 to Type 4, on the basis of an oxidation level of a geranyl side chain, in addition to the involvement of the fatty acid chain ( Figure 1). ...
Article
The first total syntheses of hericenones C–H and “putative 3-hydroxyhericenone F” were achieved. Highlights of the synthesis include the straightforward construction of the resorcinol core and geranyl side chain, assembly of the natural product skeleton by sequential O-geranylation and a clay/zeolite-mediated O → C rearrangement reaction, and a biomimetic cyclization to form a variety of bicyclic natural hericenones and their congeners. The structure of the “putative 3-hydroxyhericenone F” was revised as the 5-exo cyclization product (named: hericenone Z) of epoxyhericenone C through in-depth analyses of the cyclization modes in addition to NMR spectroscopic studies. To gain insights into the biological functions of geranyl-resorcinols in Hericium erinaceus, potential neuroprotective effects against endoplasmic reticulum (ER) stress-dependent cell death were evaluated systematically to clarify a fundamental structure–activity relationship. Among the compounds assayed, the linoleate-containing hericenone analogue, i.e., the regioisomer of hericene D, was found to possess the most potent neuroprotective effect against tunicamycin and thapsigargin-induced ER stress-dependent cell death.
... They have been found to have anti-obesity properties which decrease fat cell number and improve body fat condition [245]. They also have strong antiplatelet activity [246]. It is important to note that hericenones have only been reported in the fruiting bodies of H. erinaceus, while erinacines have been found only in mycelium [238]. ...
Article
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Macrofungi production and economic value have been increasing globally. The demand for macrofungi has expanded rapidly owing to their popularity among consumers, pleasant taste, and unique flavors. The presence of high quality proteins, polysaccharides, unsaturated fatty acids, minerals, triterpene sterols, and secondary metabolites makes macrofungi an important commodity. Macrofungi are well known for their ability to protect from or cure various health problems, such as immunodeficiency, cancer, inflammation, hypertension, hyperlipidemia, hypercholesterolemia, and obesity. Many studies have demonstrated their medicinal properties, supported by both in vivo and in vitro experimental studies, as well as clinical trials. Numerous bioactive compounds isolated from mushrooms, such as polysaccharides, proteins, fats, phenolic compounds, and vitamins, possess strong bioactivities. Consequently, they can be considered as an important source of nutraceuticals. Numerous edible mushrooms have been studied for their bioactivities, but only a few species have made it to the market. Many species remain to be explored. The converging trends and popularity of eastern herbal medicines, natural/organic food product preference, gut-healthy products, and positive outlook towards sports nutrition are supporting the growth in the medicinal mushroom market. The consumption of medicinal mushrooms as functional food or dietary supplement is expected to markedly increase in the future. The global medicinal mushroom market size is projected to increase by USD 13.88 billion from 2018 to 2022. The global market values of promising bioactive compounds, such as lentinan and lovastatin, are also expected to rise. With such a market growth, mushroom nutraceuticals hold to be very promising in the years to come.
... Phenolics compounds in H. erinaceus could also promote the synthesis of nerve growth factors, such as Hericenone C, Hericenone D, Hericenone E, and Hericenone H [12,13]. Hericenones A and B showed cytotoxicity against HeLa cells [11]. In addition, Hericenone B was found to be a potential antiplatelet aggregation agent [40]. Steroids in H. erinaceus could activate the transcriptional activity of PPARs, PPARα, and PPARc, such as erinarols A and erinarols B. In addition, nucleosides and flavonoids may be the main active components of H. erinaceus. ...
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Hericium erinaceus is a precious edible and medicinal fungus with high nutritional value. It has many functions, such as enhancing immunity, antitumor antioxidation, antihyperglycemic, antihyperlipidemic, and protecting gastric mucosa. However, there are few researches about the H. erinaceus compounds. In this paper, ultraperformance liquid chromatography tandem high-resolution mass spectrometry (UPLC-Q-exactive-MS/MS) was used to isolate and identify the compounds in H. erinaceus. 102 compounds were identified in H. erinaceus by comparing with standard databases such as MZVault, MZCloud, and BGI Library (self-built standard Library by BGI Co., Ltd), including flavonoids, terpenoids, phenolic acids, phenylpropanoids, steroids, organic acids, and amino acids.
... Moreover, isolated compounds from the ethanolic extract of Hericium erinaceus (lion's mane) mushroom; hericenone B ( Figure 17) significantly inhibited 3 µg/mL collagen activated human isolated platelet aggregation with an IC50 value of 3 µM [159]. In an animal study, davallialactone (Figure 18), isolated from Inonotus xeranticus mushroom, significantly reduced rat isolated platelet aggregation stimulated by thrombin (0.1 U/mL), collagen (2.5 µg/mL) and ADP (10 µM) in a dose-dependent manner. ...
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Cardiovascular diseases (CVDs) are a primary cause of deaths worldwide. Thrombotic diseases, specifically stroke and coronary heart diseases, account for around 85% of CVDs-induced deaths. Platelets (small circulating blood cells) are responsible for the prevention of excessive bleeding upon vascular injury, through blood clotting (haemostasis). However, unnecessary activation of platelets under pathological conditions, such as upon the rupture of atherosclerotic plaques, results in thrombus formation (thrombosis), which can cause life threatening conditions such as stroke or heart attack. Therefore, antiplatelet medications are usually prescribed for people who are at a high risk of thrombotic diseases. The currently used antiplatelet drugs are associated with major side effects such as excessive bleeding, and some patients are resistant to these drugs. Therefore, numerous studies have been conducted to develop new antiplatelet agents and notably, to establish the relationship between edible plants, specifically fruits, vegetables and spices, and cardiovascular health. Indeed, healthy and balanced diets have proven to be effective for the prevention of CVDs in diverse settings. A high intake of fruits and vegetables in regular diet is associated with lower risks for stroke and coronary heart diseases because of their plethora of phytochemical constituents. In this review, we discuss the impacts of commonly used selected edible plants (specifically vegetables, fruits and spices) and/or their isolated compounds on the modulation of platelet function, haemostasis and thrombosis.
... Гериценон B, полученный из гриба H. erinaceum, способен ингибировать агрегацию тромбоцитов [49]. H. erinaceum может регулировать функции нервной, пищеварительной, кровеносной и иммунной систем организма, что способствует общему здоровью человека [50]. ...
Article
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Medicinal mushrooms have become an attractive topic due to their bioactive compounds potentially useful for therapeutic use. Among the growing popularity of medicinal mushrooms is Hericium erinaceus. Hericium erinaceus is a medicinal edible mushroom with a long history of use in traditional Chinese medicine as well as in other countries of the East. Along with this, several of its biologically active compounds served as the basis for the creation of nutritional supplements. Its fruiting bodies and mycelium are rich in active substances that promote health. Tests of substances extracted from this fungus in animals and in vitro have given good results. They are beginning to be used in the treatment of cancer, liver diseases, Alzheimer’s and Parkinson’s diseases, and wound healing. They improve cognitive abilities, support the nervous and immune systems.
... Furthermore a more detailed investigation of the anti-thrombogenic activities of I. obliquus, L. officinalis, L. sulphureus and P. betulinus should be performed. A comparison of their activities e.g. against different serine proteases including trypsin, thrombin and prolyl endopeptidase (Amor & Villasen 2004) could reveal their substrate specificity (Mori et al. 2010) which will be a key factor for a successful application. (Campbell et al. 2008(Campbell et al. ), © 2008. ...
Thesis
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This thesis demonstrates the pharmaceutical potential of aqueous extracts of European polypores as well as their effects on the inflammatory response and their anti-thrombogenic properties. Furthermore the feasibility of producing an enzyme functionalised antibacterial nanofibrous wound dressing containing active constituents of polypores that participate in the healing process is demonstrated.
... A growing interest has also been expressed in the use of mushrooms as functional foods [13,14], and, in recent decades, certain mushroom species have been experimentally found to exert antiplatelet effects through different pathways. For example, an extract of Hericium erinaceus was found to selectively impede collagen signaling from GPIIb/Ia [15], which is an extract of Phellinus baummii suppressed collagen-5 diphosphateinduced, thrombin-5 diphosphateinduced, and adenosine-5 diphosphateinduced aggregation [16]. A methanol extract of Pleurotus florida inhibited adenosine-5 diphosphate-induced aggregation in isolated human platelets [17] while a dry extract of Stereum hirsutum diminished platelet activation by blocking the thrombin active site [18]. ...
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Cardiovascular diseases remain the leading global cause of mortality indicating the need to identify all possible factors reducing primary and secondary risk. This study screened the in vitro antiplatelet and anticoagulant activities of hot water extracts of eight edible mushroom species (Agaricus bisporus, Auricularia auricularia-judae, Coprinus comatus, Ganoderma lucidum, Hericium erinaceus, Lentinula edodes, Pleurotus eryngii, and Pleurotus ostreatus) increasingly cultivated for human consumption, and compared them to those evoked by acetylsalicylic acid (ASA). The antioxidant capacity and concentration of polysaccharides, phenolic compounds, organic acids, ergosterol, macro elements, and trace elements were also characterized. The most promising antiplatelet effect was exhibited by A. auricularia-judae and P. eryngii extracts as demonstrated by the highest rate of inhibition of adenosine-5-diphosphate (ADP)-induced and arachidonic acid (AA)-induced aggregation. The response to both extracts exceeded the one evoked by 140 µmol/L of ASA in the ADP test and was comparable to it in the case of the AA test. Such a dual effect was also observed for G. lucidum extract, even though it was proven to be cytotoxic in platelets and leukocytes. The extract of P. ostreatus revealed an additive effect on AA-induced platelet aggregation. None of the mushroom extracts altered the monitored coagulation parameters (prothrombin time, prothrombin ratio, and International Normalized Ratio). The effect of mushroom extracts on platelet function was positively related to their antioxidative properties and concentration of polysaccharides and ergosterol, and inversely related to zinc concentration. The study suggests that selected mushrooms may exert favorable antiplatelet effects, highlighting the need for further experimental and clinical research in this regard.
... There are different types of hericenones. While most of all hericenones show stimulating activity for the biosynthesis of NGF in astrocytes, hericenone B has been reported to prevent thrombosis, and considered to be effective for the protection from cerebrovascular disturbance (29). This function might also contribute to the improvement of the cognitive functions because cerebral blood flow is regarded as an important factor to dementia. ...
Article
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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The secondary metabolites from Hericium erinaceus are well-known to have neurotrophic and neuroprotective effects. Isohericerinol A (1), isolated by our colleagues from its fruiting parts has a strong ability to increase the nerve growth factor secretion in C6 glioma cells. The current work describes the total synthesis of 1 and its regioisomer 5 in a few steps. We present two different approaches to 1 and a regiodivergent approach for both 1 and 5 by utilizing easily accessible feedstocks. Interestingly, the natural product 1, regioisomer 5, and their intermediates exhibited potent neurotrophic activity in in vitro experimental systems. Thus, these synthetic strategies provide access to a systematic structure-activity relationship study of natural product 1.
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A practical route to 6-bromo-5,7-dihydroxyphthalide 5-methyl ether, a versatile intermediate in the synthesis of hericenones and related bioactive polyphenols, was developed. The synthesis features a combination of tandem Michael addition-Claisen condensation and CuBr2-mediated multi-step reactions. With this product in hand, total syntheses of hericenone J and 5′-deoxohericenone C (hericene A) were achieved.
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A new lectin, BfL, was purified from Bauhinia forficata seeds by ammonium sulfate fractionation, DEAE-Sephadex ion exchange chromatography, Sepharose-4B and chitin affinity chromatographies and Superdex 75 size exclusion chromatography. The molecular homogeneity and purity of BfL were assessed by reversed-phase HPLC. BfL appeared as a single band of approximately 27.0 kDa on SDS-PAGE under non-reducing and reducing conditions, and its molecular weight was determined to be 27,850 Da by LC/ESI-MS. BfL is a glycoprotein with a carbohydrate content of 6.24% determined by the phenol–sulfuric acid method. Fetuin, asialofetuin, thyroglobulin and azocasein inhibited the hemagglutinating activity of BfL, whereas saccharides did not. BfL hemagglutinating activity was stable at 100 °C for 30 min, pH-dependent, with the highest activity at pH 6.0, and metal-independent. The primary structure of BfL shows similarity with other lectins from the genus Bauhinia. Deconvolution of the BfL circular dichroism (CD) spectrum indicated the presence of α-helix and β structures. BfL increases coagulation time, but this effect is not related to human plasma kallikrein or human factor Xa inhibition. BfL also inhibits ADP- and epinephrine-induced platelet aggregation in a dose-dependent manner and is the only currently described lectin from Bauhinia that exhibits anticoagulant and antiplatelet aggregating properties.
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This study aimed to pharmacologically identify and characterize α2-adrenoceptors and imidazoline (I) receptors (I1- and I2-subtype) on canine, feline, bovine, equine, murine, and leporine platelet membranes. Saturation binding studies with both (3)H-yohimbine and (3)H-clonidine showed that α2-adrenoceptors were expressed on canine, leporine, feline, and murine platelets but not on bovine and equine platelets. In competition studies, the rank order of affinity of 6 compounds for canine platelet α2-adrenoceptors was similar to that of potency at α2A-subtype reported in human platelets. Saturation binding studies in the presence of norepinephrine showed that canine, feline, bovine, and equine platelets had I1-receptors defined by (3)H-clonidine binding, but neither murine nor leporine platelets had I1-receptors; whereas, platelets of all species had I2-receptors defined by (3)H-idazoxan binding. In competition studies, more potent compounds displayed biphasic competition curves with (3)H-clonidine. The rank orders of affinity of I1 compounds for high-affinity components of I1-receptors of canine, feline, bovine, and equine platelets and I2-receptors of all species platelets were similar to those of compounds for high-affinity components reported in human I1- and I2-receptors, respectively. Guanine nucleotides inhibited the high-affinity component of naphazoline binding to canine I1-receptors, but not to I2-receptors. Furthermore, guanine nucleotides dose-dependently inhibited (3)H-clonidine binding to I1-receptors; whereas, they did not interfere with (3)H-idazoxan binding to I2-receptors, supporting the notion that Il-receptors may belong to a G protein-coupled receptor superfamily in canine platelets. Interspecific variations of platelet α2-adrenoceptor and imidazoline receptor expressions may explain different platelet responses to catecholamines and imidazoline α-adrenergic agents.
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Basidiomycetes has recently attracted considerable attention for its various physiological activities, such as antitumor, antioxidant and immunostimulating activities. Compounds isolated from fruit body of Hericium erinaceum, commonly called Yamabushitake in Japan, have interesting biological activities such as cytotoxic effectors on cancer cell (HeLa cells) and stimulators of synthesis of nerve growth factor. It is necessary for the cultivation of the fruit body of mushroom to control light, temperature, humidity. Otherwise, mycelia cultivation needs only temperature control. H. erinaceum cultivated by submerged culture have similar physiological activities to the fruit body of H. erinaceum, which suggests cultured mycelia can potentially become a promoter of synthesis of nerve growth factor. In this study, we used whey which is by-products of cheese-making process as an alternative nitrogen source in submerged cultivation of H. erinaceum mycelia, and then dry cell weight (DCW) and DCW productivity of whey medium were compared with those of chemical nutrient medium. When whey was used as a nitrogen source, DCW and DCW productivity are 1.5 times higher than those of chemical nutrient medium, 5.99 g/L and 0.60 g/L/day, respectively. It was suggested that whey could be used as an alternative nitrogen source and a growth promoting factor in H. erinaceum mycelia cultivation.
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Isopropyl carbamates derived from benzylamines provide isoindolinones by treatment with phosphorus pentoxide at room temperature. Utility of this Bischler-Napieralski-type cyclization and a new mechanism involving a carbamoyl cation for rationalization of this smooth conversion are discussed.
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HEG-5, a novel glycoprotein with hemagglutinating activity, was firstly isolated and purified from the cultured mycelia of Hericium erinaceus CZ-2. SDS-PAGE, Native-PAGE and MALDI-TOF-MS proved that HEG-5 was a single band with the molecular weight of approximately 14.4 kDa. HEG-5 had the protein: polysaccharide ratio of approximately 10: 1 (%/%) and contained D-glucose, L- rhamnose, D- galactose and D-mannose with a molar ratio of 1.00: 1.09: 2.45: 7.14 in polysaccharide fraction. HEG-5 was an acidic glycoprotein with a PI value of 6.3 and the higher content of acidic amino acids (Asp, 12.42 ± 0.25% and Glu, 12.24 ± 0.26%) in protein fraction. FT-IR and NMR spectra revealed that HEG-5 contained the protein and carbohydrate portions with (1→4)-linked β-galactose residues and β-linked glucose residues. Circular dichroism (CD) demonstrated that HEG-5 was a β-sheet predominant glycoprotein. Hemagglutination assay proved it was a thermo-unstable glycoprotein. The HEG-5 structural novelty was finally presented by protein sequencing and modeling by using MALDI-TOF-MS, NCBI blast search and online SWISS-MODEL Workspace service.
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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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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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We studied the effect of the maturation stage on the chemical compositions and macrophage activation activity of polysaccharides from the culinary-medicinal mushroom Hericium erinaceus. Results showed that total polysaccharides increased, whereas protein content decreased with the maturation stage development of fruiting body. Nine polysaccharide fractions, 3 from each of the maturity stages IV (small fungal spine stage), V (mid-fungal spine stage) and VI (mature), were prepared using the gradient ethanol precipitation method. The polysaccharide fraction HP4A isolated from the maturating-stage (stage IV) fruiting body had a significant difference from the fractions HP5A (stage V) and HP6A (stage VI) in the molecular weight distribution and monosaccharide compositions. Immunostimulating tests revealed that the polysaccharide fraction HP6 isolated from the mature stage (stage VI) fruiting body presented higher macrophage activation activity. Our findings provided important information for the harvest and use of H. erinaceus with higher qualities and functional benefits.
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Hericium erinaceus (commonly known as lion’s mane mushroom) is an edible mushroom used in traditional Chinese medicine. It is a prolific producer of diverse bioactive metabolites with neuroprotective and neuroregenerative properties (e.g. β-glucan polysaccharides, hericenones, erinacine terpenoids, isoindolinones, sterols, and myconutrients). Because of its anti-inflammatory properties and promotion of nerve growth factor (NGF) gene expression and neurite (axon or dendrite) outgrowth, H. erinaceus is used for the treatment of Alzheimer's as well as Parkinson's diseases. This review provides a comprehensive account of the bioactive compounds from H. erinaceus (both from the fruit bodies and mycelia) and their biological activities such as neuroprotective functions, cytotoxicity, anticarcinogenic, antidiabetic, antimicrobial, and herbicidal activities. Keywords – Alzheimer’s disease – anticancer agents – antidiabetic – anti-inflammatory – antimicrobial – erinacine terpenoids – herbicidal – hericenone – neurite outgrowth – neuroprotection – Parkinson’s disease
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Helicium erinaceus (HE) is a fungal mushroom habiting in the mountainous areas of northeast territories. HE has been used in the traditional folk medicines and medicinal cuisine in China, Korea and Japan. It has been implicated in a variety of physiological functions such as anti-aging, anti-cancer, anti-gastritis, anti-metabolic diseases, etc. Hence, HE is an attractive target resource for developing not only medicines but also functional foods. Basic studies on the physiological functions and the chemical identification of its active ingredients have progressed in recent decades. In this article, we provide an overview of the biochemical and pharmacological studies of HE, especially of its antitumor and neural preserving functions, together with recent developments in the chemical analysis of its polysaccharides which comprise its major active components.
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The new epoxyisoindolinone (V) is stereoselectively synthesized from bicyclic sulfone (II) and transformed into a series of interesting products, including new compound (X) having an interesting 6-azabicyclooctane skeleton, via nucleophilic substitution reactions.
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The Himalayan forests of Uttarakhand represent a natural repository for the rich biodiversity of the Indian subcontinent. Forest resources in this region form an integral part of socio-economy and cultural practices. Mushrooms are forest products which have been used as food for a long time but very few for therapeutic purposes, which is associated to the lack of awareness and knowledge. If properly identified, these mystic organisms can be very promising in prevention and cure of various ailments. The present study is a part of macrofungal exploration carried out from 2015–2016. As a result, 15 mushroom species are identified which possess a spectrum of bioactive compounds and therapeutic potential. All of these species are morphologically described along with the habit, habitat and notes on their healing capacities.
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The culinary and medicinal mushroom Hericium erinaceus is widely consumed in Asian countries, but apparently not in the United States, for its nutritional and health benefits. To stimulate broader interest in the reported beneficial properties, this overview surveys and consolidates the widely scattered literature on the chemistry (isolation and structural characterization) of polysaccharides and secondary metabolites such as erinacines, hericerins, hericenones, resorcinols, steroids, mono- and diterpenes, and volatile aroma compounds, nutritional composition, food and industrial uses, and exceptional nutritional and health-promoting aspects of H. erinaceus. The reported health-promoting properties of the mushroom fruit bodies, mycelia, and bioactive pure compounds include antibiotic, anticarcinogenic, antidiabetic, antifatigue, antihypertensive, antihyperlipodemic, 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 the multiple health-promoting properties. A wide range of research advances and techniques are described and evaluated. The collated information and suggestion for further research might facilitate and guide further studies to optimize the use of the whole mushrooms and about 70 characterized actual and potential bioactive secondary metabolites to help prevent or treat human chronic, cognitive, and neurological diseases.
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Isoindolinones are ubiquitous structural motifs in natural products and pharmaceuticals. Establishing an efficient method for structural modification of isoindolinones could significantly facilitate new drug development. Herein, we describe copper-promoted direct amidation of isoindolinone scaffolds mediated by sodium persulfate. The method exhibits mild reaction conditions and high site-selectivity, and enables the structural modification of the drug indobufen ester with various amides with yields of 49 to 98%. It is also gram-scalable. Additionally, the reaction mechanism appears to involve a radical and a carbocationic pathway.
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The palladium-catalyzed cycloaminocarbonylation of 2-(aminomethyl)aryl tosylates with CO has been established, by which a variety of salicylaldehyde derived 2-(aminomethyl)aryl tosylates may be cyclocarbonylated in the presence of CO, to afford the corresponding substituted isoindolinones in moderate to excellent yields. Furthermore, the method is also effective for the synthesis of isoindoline-1,3-diones and 2-alkyl-1H-benzo[e]isoindol-3(2H)-ones from 2-(N-alkylcarbamoyl)aryl tosylates and 1-(aminomethyl)naphthalene-2-yl tosylates, respectively.
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A new natural product, meso-2,3-bis-(3,4,5-trimethoxybenzoyl)butane (1), together with six known lignans, saucernetin diol (2), licarin A (3), di-O-methyltetrahydrofuriguaiacin (4), ent-sauchinone (5), (–)-dihydroguaiaretic acid (6), and licarin B (7), were isolated from Saururus chinensis. Compound 2 was isolated from this plant for the first time. Compounds 1–7 were determined by spectroscopic methods. Compounds 1–3, 6, and 7 showed significant inhibitory activities on ADP-induced platelet aggregation, and compounds 5–7 showed promising neuroprotective effects on H2O2-induced injury in PC12 cells.
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Hericium erinaceus has the dual purposes of valuable diet and medicine, and it contains many active components and bio-functions. The aims of this research were to investigate microwave freeze-drying process and to compare with the other drying methods (hot air drying and freeze-drying) for qualities and antioxidant activities of H. erinaceus fruiting body. First, the drying curves of 50 g microwave freeze-drying H. erinaceus by different microwave power of 0.6, 0.8 and 1 W/g were established and they required 2.5, 2 and 1 h to dry, respectively. However, the 50°C hot air drying and conventional freeze-drying of 50 g H. erinaceus required more than 12 h and 21 h, respectively. The dried H. erinaceus was extracted by 85% alcohol and hot water, respectively, and then antioxidant activities of 20 μg/mL extracts were analyzed. The crude polysaccharide contents of microwave freeze-dried H. erinaceus were up to 5.75%. Two different freeze-dried H. erinaceus had no significant difference on total polyphenol and flavonoid contents, which were about 8-9 mg/g and 720-840 μg/g, respectively. The 20 μg/mL ethanol extracts from freeze-dried and microwave freeze-dried H. erinaceus had no significant difference on the scavenging DPPH ability (about 92-93%) and reducing power at 700 nm (about 1.3), but their reducing power were significantly higher than hot air dried H. erinaceus. The chelating iron capacities of the freeze-dried H. erinaceus were bout 87-93%. Microwave freeze-dried H. erinaceus maintained good antioxidant activities as the traditional freeze-dried H. erinaceu; however, microwave freeze-drying significantly reduced drying time and saved energy.
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An efficient and practical electrochemical method for selective reduction of cyclic imides has been developed using a simple undivided cell with carbon electrodes at room temperature. The reaction provides a useful strategy for the rapid synthesis of hydroxylactams and lactams in a controllable manner, which is tuned by electric current and reaction time, and exhibits broad substrate scope and high functional group tolerance even to reduction-sensitive moieties. Initial mechanistic studies suggest that the approach heavily relies on the utilization of amines (e.g., i-Pr2NH), which are able to generate α-aminoalkyl radicals. This protocol provides an efficient route for the cleavage of C-O bonds under mild conditions with high chemoselectivity.
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HPB-3, a heteropolysaccharide, with a mean molecular weight of 1.5 × 10⁴ Da, was obtained from the maturating-stage IV, V and VI fruiting body of Hericium erinaceus, exhibited higher macrophages stimulation activities, was able to upregulate the functional events mediated by activated macrophages, such as production of nitric oxide (NO). Monosaccharide composition analysis showed that HPB-3 comprised l-fucose, d-galactose and d-glucose in the ratio of 5.2:23.9:1. Its chemical structure was characterized by sugar and methylation analysis, along with ¹H and ¹³C NMR spectroscopy, including ¹H–¹H COSY, TOCSY, NOESY, HMQC and HMBC experiments. The results indicated that HPB-3 contained a-(1/6)-linked galactopyranosyl backbone, partially with a side chain composed of α-l-fucopyranose at the O-2 position. The predicted primary structure of the polysaccharide was established as below: • Download high-res image (111KB) • Download full-size image
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Isoindolin-1-one or 1-isoindolinone framework is referred to phthalimidines or benzo fused γ-lactams of the corresponding γ-amino carboxylic acids and has been of prime interest for scientists for last several decades. 1-Isoindolinone framework is found in a wide range of naturally occurring compounds with diverse biological activities and therapeutic potential for various chronic diseases. Recent developments in synthetic methods for their procurement have opened a new era of 1-isoindolinone chemistry. This review aims to provide an alphabetical quick reference guide to only 1-isoindolinone based natural products and its variable fused, oxidized and reduced state skeleton with information for advanced chemotaxonomic analyses, cellular targets/pathways and diverse biological activities and future use for medicinal chemistry.
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Polystyrene supported palladium ([email protected]) nanoparticles (NPs) catalyzed intramolecular aminocarbonylation of 2-iodobenzamides and 2-iodobenzylanilines using bench stable Oxalic acid as in situ CO source for the synthesis of phthalimides and isoindolin-1-one is described. Low catalyst loadings (0.2 mol%, 2000 ppm Pd) with appreciable recyclability up to six cycles, external base free, Oxalic acid as inexpensive and safer in situ C1 source and vast substrate scope are some remarkable features of the present protocol. Furthermore, we scale up the present reaction up to 1.5 gram.
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Platelets are central mediators of haemostasis at sites of vascular injury, but they also mediate pathologic thrombosis. Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. They also interact with endothelial cells and leukocytes to promote inflammation, which contributes to atherosclerosis. Multiple pathways contribute to platelet activation, and current oral antiplatelet therapy with aspirin and a P2Y(12) adenosine diphosphate (ADP) receptor antagonist target the thromboxane A(2) and ADP pathways, respectively. Both can diminish activation by other factors, but the extent of their effects depends upon the agonist, agonist strength, and platelet reactivity status. Although these agents have demonstrated significant clinical benefit, residual morbidity and mortality remain high. Neither agent is effective in inhibiting thrombin, the most potent platelet activator. This lack of comprehensive inhibition of platelet function allows continued thrombus formation and exposes patients to risk for recurrent thrombotic events. Moreover, bleeding risk is a substantial limitation of antiplatelet therapy, because these agents target platelet activation pathways critical for both protective haemostasis and pathologic thrombosis. Novel antiplatelet therapies that provide more complete inhibition of platelet activation without increasing bleeding risk could considerably decrease residual risk for ischemic events. Inhibition of the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin is a novel, emerging approach to achieve more comprehensive inhibition of platelet activation when used in combination with current oral antiplatelet agents. PAR-1 inhibition is not expected to increase bleeding risk, as this pathway does not interfere with haemostasis.
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A potent platelet aggregation inducer, aggretin, was purified from Malayan-pit-viper (Calloselasma rhodostoma) venom by ionic-exchange chromatography, gel-filtration chromatography and HPLC. It is a heterodimeric protein (29 kDa) devoid of esterase, phospholipase A and thrombin-like activity. Aggretin (> 5 nM) elicited platelet aggregation with a lag period in both human platelet-rich plasma and washed platelet suspension. EDTA (5 mM), prostaglandin E1 (1 microM) and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester ('TMB-8'; 100 microM) abolished its aggregating activity, indicating that exogenous bivalent cations and intracellular Ca2+ mobilization are essential for aggretin-induced platelet aggregation. Neomycin (4 mM) and mepacrine (50 microM) completely inhibited aggretin (33 nM)-induced aggregation; however, creatine phosphate/creatine phosphokinase (5 mM, 5 units/ml) and indomethacin (50 microM) did not significantly affect its aggregating activity. Aggretin caused a significant increase of [3H]InsP formation in [3H]Ins-loaded platelets, intracellular Ca2+ mobilization and thromboxane B2 formation. Neomycin, a phospholipase C inhibitor, completely inhibited both the increase of [3H]InsP and intracellular Ca2+ mobilization of platelets stimulated by aggretin. A monoclonal antibody (6F1) directed against glycoprotein Ia/IIa inhibited platelet shape change and aggregation induced by aggretin. 125I-aggretin bound to platelets with a high affinity (Kd = 4.0 +/- 1.1 nM), and the number of binding sites was estimated to be 2119 +/- 203 per platelet. It is concluded that aggretin may act as a glycoprotein Ia/IIa agonist to elicit platelet aggregation through the activation of endogenous phospholipase C, leading to hydrolysis of phosphoinositides and subsequent intracellular Ca2+ mobilization.
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Convulxin, a powerful platelet activator, was isolated from Crotalus durissus terrificus venom, and 20 amino acid N-terminal sequences of both subunits were determined. These indicated that convulxin belongs to the heterodimeric C-type lectin family. Neither antibodies against GPIb nor echicetin had any effect on convulxin-induced platelet aggregation showing that, in contrast to other venom C-type lectins acting on platelets, GPIb is not involved in convulxin-induced platelet activation. In addition, partially reduced/denatured convulxin only affects collagen-induced platelet aggregation. The mechanism of convulxin-induced platelet activation was examined by platelet aggregation, detection of time-dependent tyrosine phosphorylation of platelet proteins, and binding studies with 125I-convulxin. Convulxin induces signal transduction in part like collagen, involving the time-dependent tyrosine phosphorylation of Fc receptor γ chain, phospholipase Cγ2, p72SYK, c-Cbl, and p36–38. However, unlike collagen, pp125FAK and some other bands are not tyrosine-phosphorylated. Convulxin binds to a glycosylated 62-kDa membrane component in platelet lysate and to p62/GPVI immunoprecipitated by human anti-p62/GPVI antibodies. Convulxin subunits inhibit both aggregation and tyrosine phosphorylation in response to collagen. Piceatannol, a tyrosine kinase inhibitor with some specificity for p72SYK, showed differential effects on collagen and convulxin-stimulated signaling. These results suggest that convulxin uses the p62/GPVI but not the α2β1 part of the collagen signaling pathways to activate platelets. Occupation and clustering of p62/GPVI may activate Src family kinases phosphorylating Fc receptor γ chain and, by a mechanism previously described in T- and B-cells, activate p72SYK that is critical for downstream activation of platelets.
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Piper longum L. has been used as a crude drug for the treatment of disorders of poor peripheral blood circulation in Asia. However, the detailed mechanism of its action has not been clarified as yet. In the present study, we examined the effects of several extracts of Piper longum L. on rabbit platelet function. Thromboxane A(2) receptor agonist U46619 caused rabbit platelet aggregation, which was potently inhibited by the ethanol or butanol extract of Piper longum L. The ethanol extract inhibited U46619-induced platelet aggregation in a concentration-dependent manner, but only weakly inhibited that induced by thrombin. The maximum response to U46619 was reduced by 100% ethanol extract concentration dependently, suggesting that the inhibitory mode of U46619-induced platelet aggregation by the ethanol extract was non-competitive. The extract also inhibited U46619-induced phosphoinositide hydrolysis with a similar concentration dependency to the platelet aggregation. Furthermore, the extract inhibited binding of [(3)H]SQ29548 to thromboxane A(2) receptor in intact platelets in a concentration-dependent manner. These results suggest that Piper longum L. contains a constituent(s) that inhibits platelet aggregation as a non-competitive thromboxane A(2) receptor antagonist.
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At sites of vascular injury, platelets come into contact with the subendothelial extracellular matrix which triggers their activation and the formation of a hemostatic plug. This process is crucial for normal hemostasis, but may also lead to pathological thrombus formation causing diseases such as myocardial infarction or stroke. The initial capture of flowing platelets is mediated by the interaction of the glycoprotein (GP) Ib-V-IX complex with von Willebrand factor (vWF) immobilized on exposed collagens. This interaction allows the binding of the collagen receptor GPVI to its ligand and to initiate cellular activation, a process that is reinforced by locally produced thrombin and soluble mediators released from platelets. These events lead to the shift of beta1 and beta3 integrins on the platelet surface from a low to a high affinity state, thereby enabling them to bind their ligands and to mediate firm adhesion, spreading, coagulant activity, and aggregation. This review summarizes the most important structural and functional properties of these adhesion receptors and briefly discusses their potential as targets for antithrombotic therapy.
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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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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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Cerebrovascular disease is a leading cause of morbidity and mortality in developed countries around the world. In the United States, there are an estimated 700,000 cases of stroke annually (of which over 85% are ischemic), costing an estimated $56.8 billion in associated treatment. Large vessel internal carotid artery stenosis is an important cause of ischemic stroke. Population-based studies have shown that the prevalence of carotid stenosis is approximately 0.5% in the sixth decade of life and increases to approximately 10% in the ninth decade. The majority of patients are asymptomatic. Asymptomatic carotid stenosis with <or=75% lumen loss carries a stroke risk of 1.3% annually, whereas the combined risk of myocardial ischemia and vascular death is as high as 10%. With diameter stenosis >75%, the combined stroke and transient ischemic attack risk increases to approximately 11% annually, with 75% of events ipsilateral to the affected artery. Other studies have also shown that the risk of stroke increases proportionately to the severity of stenosis. The risk is higher for those patients who are symptomatic. In this review, we will discuss antiplatelet agents to prevent cerebrovascular events in the context of extracranial carotid artery disease. It is beyond the scope of this article to discuss antiplatelet treatment for other etiologies of stroke.
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A double-blind, parallel-group, placebo-controlled trial was performed on 50- to 80-year-old Japanese men and women diagnosed with mild cognitive impairment in order to examine the efficacy of oral administration of Yamabushitake (Hericium erinaceus), an edible mushroom, for improving cognitive impairment, using a cognitive function scale based on the Revised Hasegawa Dementia Scale (HDS-R). After 2 weeks of preliminary examination, 30 subjects were randomized into two 15-person groups, one of which was given Yamabushitake and the other given a placebo. The subjects of the Yamabushitake group took four 250 mg tablets containing 96% of Yamabushitake dry powder three times a day for 16 weeks. After termination of the intake, the subjects were observed for the next 4 weeks. At weeks 8, 12 and 16 of the trial, the Yamabushitake group showed significantly increased scores on the cognitive function scale compared with the placebo group. The Yamabushitake group's scores increased with the duration of intake, but at week 4 after the termination of the 16 weeks intake, the scores decreased significantly. Laboratory tests showed no adverse effect of Yamabushitake. The results obtained in this study suggest that Yamabushitake is effective in improving mild cognitive impairment.
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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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Convulxin, a very potent aggregating protein from rattlesnake venom, was purified by a new procedure and its heterodimeric structure alpha 3 beta 3 was confirmed. The polypeptide N-terminal sequences of convulxin subunits were determined by Edman degradation. They are very similar and appear homologous to botrocetin from Bothrops jararaca venom and to rattlesnake lectin from Crotalus atrox venom, both being classified among the C-type lectin family. The binding of 125I-labelled convulxin to blood platelets has also been analysed under equilibrium conditions. These studies indicated that convulxin binds to platelets with a high affinity (Kd = 30 pM) on a small number of binding sites (1000 binding sites per cell). The high-affinity binding of convulxin appears specific to platelets, since it is not observed on other cell types such as neutrophils and erythrocytes. Also, the high-affinity binding of convulxin to membranes platelet is not inhibited by alpha-thrombin, fibrinogen, collagen, laminin binding inhibitor, RGDS peptide, adenosine diphosphate, platelet-activating factor-acether, serotonin or epinephrine. This, together with the recent observation that platelet activation by convulxin is partially mediated by phospholipase C and involves other mechanisms as well, indicates that convulxin may interact with a specific platelet acceptor (receptor) protein which has yet to be characterized.
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Recent in vivo studies have highlighted the dynamic and complex nature of platelet thrombus growth and the requirement for multiple adhesive receptor-ligand interactions in this process. In particular, the importance of von Willebrand factor (VWF) in promoting both primary adhesion and aggregation under high shear conditions is now well established. In general, the efficiency with which platelets adhere and aggregate at sites of vessel wall injury is dependent on the synergistic action of various adhesive and soluble agonist receptors, with the contribution of each of the individual receptors dependent on the prevailing blood flow conditions. In this review, we will discuss the major platelet adhesive interactions regulating platelet thrombus formation under high shear, with specific focus on the VWF (GPIb and integrin alphaIIbbeta3) and collagen receptors (GPVI and integrin alpha2beta1). We will also discuss the signaling mechanisms utilized by these receptors to induce platelet activation with specific emphasis on the role of cytosolic calcium flux in regulating platelet adhesion dynamics. The role of soluble agonists in promoting thrombus growth will be highlighted and a model to explain the synergistic requirement for adhesive and soluble stimuli for efficient platelet aggregation will be discussed.
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Platelets play a central role in the hemostatic process and consequently are similarly involved in the pathological counterpart, thrombosis. They adhere to various subendothelial proteins, exposed either by injury or disease, and subsequently become activated by the thrombogenic surface or locally produced agonists. These activated platelets aggregate to form a platelet plug, release agonists which recruit more platelets to the growing thrombus, and provide a catalytic surface for thrombin generation and fibrin formation. These platelet-rich thrombi are responsible for the acute occlusion of stenotic vessels and ischemic injury to heart and brain. A range of anti-platelet drugs are currently used, both prophylactically and therapeutically, in regimens to manage thrombo-embolic disorders. These include inhibitors of the generation, or effects, of locally produced agonists; several large clinical trials have supported roles for cyclooxygenase inhibitors, which prevent thromboxane generation, and thienopyridine derivatives, which antagonize ADP receptors. Similarly intravenous alpha IIb beta 3 antagonists have been shown to be effective anti-thrombotics, albeit in highly selective situations; in contrast, to date studies with their oral counterparts have been disappointing. Recent advances in understanding of platelet physiology have suggested several novel, if yet untested, targets for anti-platelet therapy. These include the thrombin receptor, the serotonin handling system, and the leptin receptor.
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Piper longum L. has been used as a crude drug for the treatment of the disorder of peripherally poor blood circulation in Asia. In the present study, we examined the effect of piperlongumine, a constituent of P. longum L., on rabbit platelet aggregation. Piperlongumine concentration-dependently inhibited platelet aggregation induced by thromboxane A(2) receptor agonist U46619, but it only slightly inhibited thrombin-induced one. Piperlongumine also inhibited U46619-induced phosphatidylinositol hydrolysis and the binding of [(3)H]SQ29548 to thromboxane A(2) receptor with a similar concentration-dependency to the aggregation. It is assumed that piperlongumine inhibits platelet aggregation as a thromboxane A(2) receptor antagonist.
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Platelets have important roles in atherosclerosis and thrombosis and their inhibition reduces the risk of these disorders. There is still a need for platelet inhibitors affecting pathways that reduce thrombosis and atherosclerosis while leaving normal hemostasis relatively unaffected, thus reducing possible bleeding complications. Although combinations show progress in achieving these goals none of the present inhibitors completely fulfill these requirements. Collagen receptors offer attractive possibilities as alternative targets at early stages in platelet activation. Three major collagen receptors are assessed in this review; the alpha2beta1 integrin, responsible primarily for platelet adhesion to collagen; GPVI, the major signaling receptor for collagen; and GPIb-V-IX, which is indirectly a collagen receptor via von Willebrand factor. Several thrombosis models and experimental approaches suggest that all three are interesting targets and merit further investigation.
Article
Collagen, one of the major proteins of sub-endothelial vasculature get exposed following endothelium denudement, is a potent stimulator of platelet adhesion and aggregation. Adhesion of platelets following endothelial injury is the primary event usually associated with uncontrolled platelet activation culminating into intravascular thrombosis, thus needs to be intervened to prevent the pathology related to various peripheral, myocardial and cerebral ischemic episodes. Recent advances in the understanding of collagen mediated platelet adhesion and aggregation have led to the identification of two prominent receptors, glycoprotein Ia/IIa (GPIa/IIa or integrin alpha(2)beta(1)) and glycoprotein VI (GPVI) and associated intracellular signaling, which are undoubtedly the new emerging targets for the development of more effective antithrombotic drugs. The optimism for collagen antagonism is based on results obtained so far by the use of monoclonal and polyclonal antibodies, peptide inhibitors, knockouts models and collagen-mimetics in various in vitro test systems and animal models. These findings have revealed that collagen receptor inhibition is an attractive and secure strategy for the new drug development to prevent intravascular thrombosis.
Article
Platelet adhesion to vascular subendothelium, mediated in part by interactions between collagen and glycoprotein VI (GPVI) complexed with Fc receptor gamma-chain, is crucial for thrombus formation. Antiplatelet therapy benefits patients with various thrombotic and ischemic diseases, but the safety and efficacy of existing treatments are limited. Recent data suggest GPVI as a promising target for a novel antiplatelet therapy, for example, GPVI-specific Abs that deplete GPVI from the surface of platelets. Here, we characterized GPVI-specific auto-Abs (YA-Abs) from the first reported patient with ongoing platelet GPVI deficiency caused by the YA-Abs. To obtain experimentally useful human GPVI-specific mAbs with characteristics similar to YA-Abs, we generated human GPVI-specific mouse mAbs and selected 2 representative mAbs, mF1201 and mF1232, whose binding to GPVI was inhibited by YA-Abs. In vitro, mF1201, but not mF1232, induced human platelet activation and GPVI shedding, and mF1232 inhibited collagen-induced human platelet aggregation. Administration of mF1201 and mF1232 to monkeys caused GPVI immunodepletion with and without both significant thrombocytopenia and GPVI shedding, respectively. When a human/mouse chimeric form of mF1232 (cF1232) was labeled with a fluorescent endocytosis probe and administered to monkeys, fluorescence increased in circulating platelets and surface GPVI was lost. Loss of platelet surface GPVI mediated by cF1232 was successfully reproduced in vitro in the presence of a cAMP-elevating agent. Thus, we have characterized cAMP-dependent endocytosis of GPVI mediated by a human GPVI-specific mAb as what we believe to be a novel antiplatelet therapy.