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Extract of Ganoderma lucidum prolongs sleep time in rats

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Abstract

Ganoderma lucidum (Ling Zhi) is a basidiomycete white-rot macrofungus that has been used as a tranquilizing agent (i.e., An-Shen effect) for the treatment of restlessness, insomnia, and palpitation in China for hundreds of years. The present study aimed to investigate whether Ganoderma lucidum extract (GLE) influences the sleep of freely moving rats and the potential mechanism. Ganoderma lucidum extract was extracted from fruiting bodies of Ganoderma lucidum. Rats were treated with GLE orally for 3 days, and on the third day, electroencephalographic and electromyographic recordings were made for 6h from 9:00 p.m. to 3:00 a.m. in freely moving rats. Sleep parameters were analyzed using SleepSign software. Tumor necrosis factor-α (TNF-α) levels were measured using the enzyme-linked immunosorbent assay. Three-day administration of GLE significantly increased total sleep time and non-rapid eye movement (NREM) sleep time at a dose of 80 mg/kg (i.g.) without influencing slow-wave sleep or REM sleep in freely moving rats. TNF-α levels were significantly increased concomitantly in serum, the hypothalamus, and dorsal raphe nucleus. The hypnotic effect of GLE (80 mg/kg, i.g.) was significantly inhibited by intracerebroventricular injection of TNF-α antibody (2.5 μg/rat). Co-administration of GLE (40 mg/kg, i.g.) and TNF-α (12.5 ng/rat, i.c.v.), both at ineffective doses, revealed an additive hypnotic effect. These results suggest that GLE has hypnotic effects in freely moving rats. The mechanism by which the extract promoted sleep remains unclear, but this effect appears to be primarily related to the modulation of cytokines such as TNF-α. Furthermore, these data at least partially support the ethnomedical use of Ganoderma lucidum.

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... The studies on mice and rats have shown that extract from Reishi significantly prolongs both the total sleep time and sleep time without non rapid eye movements (NREM). It is also suggested that Reishi supplementation may evoke a hypnotic effect [54]. One of the unique aspects of Reishi is its beneficial effect on the human organism. ...
... Badania na myszach i szczurach wykazały, że ekstrakt z Reishi znacząco wydłuża zarówno całkowity czas snu, jak i czas snu bez szybkich ruchów gałek ocznych (NREM). Su geruje się też, że suplementacja Reishi może wywoływać efekt hipnotyczny [54]. Jednym z unikalnych aspektów Reishi jest to, że nie tylko owocnik wykazuje korzystne oddziaływanie na organizm. ...
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Physically active people and athletes always seek new dietary interventions in­cluding natural products, hoping to improve their condition and gain support, allowing them to meet their settled goals. Potential benefits of using medicinal mushrooms (ganotherapy), resulting from their proven efficacy, seem extremely promising for athletic performance. They may evoke a justified interest, especially among competitors from western countries where the tradition of using mushrooms for health reasons is virtually nonexistent. The goal of the paper is to present the current knowledge of selected medicinal mushrooms among the population involved in excessive physical exercise and the range of research in the above-mentioned domain.
... Recording electroencephalography (EEG) in animals is the most important technique for revealing the sleep architectures of hypnotics [12, 13] . Further, the sleep-enhancing effects of various treatments have been investigated using an EEG study in rodents [14]. Sleep is composed of two principal phases in mammals: rapid eye movement (REM) sleep and non-REM (NREM) sleep. ...
... Thus, it is important that both PCE and PA increase sleeping behaviors via GABAAergic mechanisms in the CNS [9]. In terms of herbal insomnia treatments, research has revealed that Ganoderma lucidum prolongs sleep time in rats in a similar fashion [14]. PCE and PA are used for their somnogenic effects. ...
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Poria cocos is a well-known traditional Chinese traditional medicine (TCM) that grows around roots of pine trees in China, Korea, Japan, and North America. Poria cocos has been used in Asian countries to treat insomnia as either a single herb or part of an herbal formula. In a previous experiment, pachymic acid (PA), an active constituent of Poria cocos ethanol extract (PCE), increased pentobarbital-induced sleeping behaviors. The aim of this experiment was to evaluate whether or not PCE and PA modulate sleep architectures in rats as well as whether or not their effects are mediated through GABA(A)-ergic transmission. PCE and PA were orally administered to individual rats 7 days after surgical implantation of a transmitter, and sleep architectures were recorded by Telemetric Cortical encephalogram (EEG) upon oral administration of test drugs. PCE and PA increased total sleep time and non-rapid eye movement (NREM) sleep as well as reduced numbers of sleep/wake cycles recorded by EEG. Furthermore, PCE increased intracellular chloride levels, GAD65/67 protein levels, and alpha-, beta-, and gamma-subunits of GABA(A) receptors in primary cultured hypothalamic neuronal cells. These data suggest that PCE modulates sleep architectures via activation of GABA(A)-ergic systems. Further, as PA is an active component of PCE, they may have the same pharmacological effects.
... This may influence its perception as a nutraceutical, as many people believe in the effects claimed by TCM practitioners. For example, the usage of G. lucidum for its An-Shen effect (tranquilising) was only recently supported with evidence from an animal model study (Cui et al., 2012) yet has been used for centuries for its tranquilising effect. This study showed that the administration of G. lucidum extract increased total sleep time and non-rapid eye movement significantly in rats, with a possible mechanism related to TNF-a (Cui et al., 2012). ...
... For example, the usage of G. lucidum for its An-Shen effect (tranquilising) was only recently supported with evidence from an animal model study (Cui et al., 2012) yet has been used for centuries for its tranquilising effect. This study showed that the administration of G. lucidum extract increased total sleep time and non-rapid eye movement significantly in rats, with a possible mechanism related to TNF-a (Cui et al., 2012). More evidence of this sort is required to appropriately support TCM claims about the health benefits of G. lucidum products. ...
... Indeed, a randomized controlled trial described that the polysaccharide extract of Ganoderma lucidum improved the insomnia severity scores in patients with neurasthenia [42]. Moreover, Ganoderma lucidum extract has been shown to increase total sleep time and nonrapid eye movement sleep time in animal studies [43,44], with a probable mechanism linked to the modulation of cytokines such as tumor necrosis factor-α [44]. ...
... Indeed, a randomized controlled trial described that the polysaccharide extract of Ganoderma lucidum improved the insomnia severity scores in patients with neurasthenia [42]. Moreover, Ganoderma lucidum extract has been shown to increase total sleep time and nonrapid eye movement sleep time in animal studies [43,44], with a probable mechanism linked to the modulation of cytokines such as tumor necrosis factor-α [44]. ...
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Elderly people are particularly vulnerable to respiratory tract infections, so natural strategies to ameliorate the duration and severity of these infections are of great interest in this population. The objective of this study is to evaluate the efficacy of the consumption of a combination of elderberry and reishi extracts on the incidence, severity, and duration of respiratory tract infections in a group of healthy elderly volunteers. A randomized, double-blind, placebo-controlled pilot study was performed during the winter season. A group of 60 nursing home residents ≥65 years of age was randomly assigned to receive a combination of 1.5 g of elderberry +0.5 g of reishi or a placebo daily for 14 weeks. Data about the health conditions of the volunteers were evaluated and recorded by a medical doctor every 2 weeks. The incidence of respiratory infections was similar in both groups. However, volunteers in the extract group presented a significantly lower duration of common cold events (2.5 vs. 4.8 days, p = 0.033).and a significantly lower probability of having a high severity influenza-like illness event (p = 0.039). Moreover, the incidence of sleep disturbances was significantly lower in the extract group (p = 0.049). Therefore, the administration of a combination of elderberry and reishi extracts to the elderly population during the winter season might be used as a natural strategy to reduce the duration and severity of respiratory tract infections.
... Known as the "elixir of life" or "mushroom of immortality," officially used as a dietary supplement, this mushroom presents popular indications for "improving memory," "retarding senility," among other purposes [18][19][20][21]. Bioactive compounds such as triterpenes, lectins, and polysaccharides have been described in their composition [21][22][23][24]. ...
... A recent study reported that G. lucidum is able to act on free radicals and suppress lipid peroxidation, normalizing the balance between antioxidant defenses and reactive oxygen species, thus reducing oxidative stress [19]. In fact, studies have confirmed therapeutic activities of G. lucidum in the CNS, such as antidepressant action, cognitive improvement, and hypnotic properties, but the mechanisms have not yet been elucidated [22,24]. ...
Article
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Ganoderma lucidum, mushroom used for centuries by Asian peoples as food supplement, has been shown interesting biological activities, including over the Central Nervous System. Besides, these mushroom bioactive compounds present antioxidant and anti-inflammatory activities. On the side, binge drinking paradigm consists of ethanol exposure that reflects the usual consumption of adolescents, which elicits deleterious effects, determined by high ethanol consumption, in a short period. In this study, we investigated whether the Aqueous Extract of G. lucidum (AEGl) reduces the behavioral disorders induced by alcohol. Male (n = 30) and female Wistar rats (n = 40), seventy-two days old, were used for behavioral/biochemical and oral toxicity test, respectively. Animals were exposed to 5 binges (beginning at 35 days old) of ethanol (3 g/kg/day) or distilled water. Twenty-four hours after the last binge administration, animals received AEGl (100 mg/kg/day) or distilled water for three consecutive days. After treatment protocol, open field, elevated plus maze, forced swim, and step-down inhibitory avoidance tests were performed. Oxidative stress parameters were measured to evaluate the REDOX balance. Our results demonstrated that AEGl elicited the recovery of spontaneous horizontal exploration capacity, anxiogenic- and depressive-profile, as well as short-term memory damage induced by binge-ethanol exposure. The behavioral effects of the extract were associated to the reequilibrium of the animals' REDOX balance. Thus, AEGl, a medicinal mushroom, ameliorates behavioral alteration on a model of motor, cognitive and psychiatric-like disorders induced by binge drinking paradigm and emerges as a useful tool as a food supplement in the management of disorders of alcoholic origin.
... Además, diferentes investigaciones han demostrado que el consumo de reishi puede aumentar la calidad del sueño Permiso otorgado por the American Herbal Pharmacopoeia el 20 de octubre de 2015. 45], disminuir la sensación de cansancio [46] y, en general, mejorar el estado de bienestar físico y consecuentemente la calidad de vida de las personas afectadas de FM, gracias también a su actividad sobre el potenciamiento del sistema inmunitario y de defensa celular [47]. De hecho, investigaciones tanto in vitro como in vivo destacan que el consumo de reishi incrementa las defensas del organismo [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65], defiende las células gracias a su elevado contenido de factores antioxidantes [48,[66][67][68][69][70][71][72][73][74], mejora el sistema circulatorio disminuyendo la formación de trombos [75], ayuda a regular los niveles de azúcares y lípidos en la sangre (glucosa, colesterol y triglicéridos) [76][77][78][79][80] y disminuye la presión arterial [78,81]. ...
... En este contexto un estudio ha demostrado en ratas que el GL aumenta significativamente el tiempo total de sueño y la fase de sueño no-REM en dosis de 80 mg/kg, sin influenciar la fase de sueño REM. Aunque los mecanismo de acción del GL sobre el sueño no hayan sido aclarados, parece que sus efectos estarían relacionados con el aumento de las citoquinas, unos mediadores inmunológicos proteicos involucrado en la modulación del sueño [45]. Otro estudio con ratones [104] ha demostrado que el GL disminuye la fase de latencia del sueño y aumenta la duración de la fase de sueño ligero no-REM, sin influenciar la fase de sueño REM. ...
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Fibromyalgia is a chronic syndrome of unknown etiology characterized by widespread musculoskeletal pain which affects between 2% and 5% of the world population. The main symptoms are fatigue, decreased physical fitness, poor sleep and depression, among many others. Likewise, patients with fibromyalgia often suffer obesity problems, that represent a risk factor for the onset of other cardiovascular problems as hypertension and type 2 diabetes. These symptoms can lead to decreased Health Related Quality of Life and a high level of impediment. To date, it has not been identified an effective treatment for this syndrome yet. The best therapeutic strategy involves a multidisciplinary approach based on drug treatment, physical activity and psychological therapy. Recent studies have also started to assess functional food in order to complement the actual therapy. Reishi is the common name of a mushroom produced by the fungus called Ganoderma lucidum (Curt .: Fr.) P. Karst. This mushroom has proven to be useful to improve the quality and quantity of sleep, raise the defense levels of the organism, reduce cholesterol, triglycerides, glucose, weight and blood pressure and, finally, increase physical performance. To date, to our knowledge, there are no studies aimed to assess the effect of reishi on the fibromyalgic population. The main objective of the study was to evaluate the effects of 6 grams of micro-milled Ganoderma lucidum powder administered by oral route on the following variables: pain, quality of sleep and the inability of patients with fibromyalgia. Secondly, we have evaluated the effects of 6 grams of micro-milled Ganoderma lucidum powder in comparison with 6 grams of Carob (Ceratonia siliqua) flour on the following variables: happiness, depression, health related quality of life, perception of improvement, fitness, blood glucose, cholesterol and triglycerides, blood pressure and body composition. Seventy fibromyalgic patients were included in a randomized clinical trial with an experimental group and an active placebo group for the pain and sleep variables. The experimental group toke 2 doses of 3 grams of reishi daily, one at breakfast and another at dinner, for 42 days. The active placebo group toke the same dose of carob flour. Results showed that 6 daily grams of reishi decrease the impact of fibromyalgia and improve the following variables: sleep quality, happiness, perception of global clinical improvement, aerobic endurance, speed and flexibility of the lower limb. In addition, reishi may lower pain level. In conclusion, this study open a new line of investigation for the fibromyalgia treatment, since the intake of reishi could complement the actual strategy to combat the symptoms of fibromyalgia. Keywords: Fibromyalgia; Pain; Ganoderma lucidum; Ceratonia siliqua; Alternative medicine; Functional food.
... To date, G. lucidum extract has been reported to potentiate the anesthetic effect of pentobarbital, reducing spontaneous locomotor activity 4 and prolonging sleep time in rodents. 5 In clinical studies G. lucidum polysaccharides significantly improved symptoms of neurasthenia, 6 whereas spore powder had a beneficial effect on quality of life and cancer-related fatigue in patients with breast cancer. 7 Moreover, neuroprotective effects of G. lucidum have been demonstrated. ...
Article
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Ganoderma lucidum is a well-known medicinal mushroom with a long history of use. This study was designed to assess the anticonvulsant potential of an aqueous extract from cultured G. lucidum mycelium in 3 acute seizure models: timed intravenous pentylenetetrazole infusion, maximal electroshock seizure threshold, and 6-Hz-induced psychomotor seizure tests in mice. Moreover, antidepressant-like and anxiolytic-like effects of G. lucidum were evaluated using the forced swim test and the elevated plus maze test in mice, respectively. No changes in seizure thresholds in the intravenous pentylenetetrazole and maximal electroshock seizure threshold tests after acute treatment with G. lucidum extract (200-600 mg/kg) was observed. However, the studied extract (100-400 mg/kg) significantly increased the threshold for psychomotor seizures in the 6-Hz seizure test. In the forced swim test, G. lucidum (100-400 mg/kg) significantly reduced the duration of immobility. No anxiolytic-like or sedative effects were reported in mice pretreated with the extract (400-600 mg/kg). G. lucidum extract (50-2400 mg/kg) did not produce toxic effects in the chimney test (motor coordination) or grip-strength test (neuromuscular strength). Further studies are required to explain the neuropharmacological effects of G. lucidum and to identify its active ingredients that may affect seizure threshold, mood, or anxiety.
... At least 1 week prior to any sleep recordings the animals were instrumented by standard procedures as reported ( Cui et al., 2012 ). The animals were implanted chronically with stainless steel screws over the frontal-parietal cortex and a pair of wire electrodes through the nuchal muscles for recording of electroencephalogram (EEG) and electromyogram (EMG), respectively. ...
Article
Background: Sleep disorders have been found to be associated with hypertension in both cross-sectional and longitudinal epidemiological studies. Tetrandrine, a major component of Stephania tetrandra, is well known as an antihypertensive agent. The anti-hypertension mechanism mainly relies on its L-type calcium channel blocking property. In the previous study, tetrandrine revealed both anti-hypertension and hypnotic effects in spontaneously hypertensive rats (SHRs). Purpose: This study aims to elucidate whether the antihypertensive mechanism of tetrandrine in SHRs is relevant to its hypnotic effect. Design/methods: Sleep-wake behavior of the SHRs was detected by electroencephalography (EEG) and electromyography (EMG) recordings. Blood pressure was measured by noninvasive blood pressure tail cuff test. Immunohistochemistry was performed to evaluate the noradrenergic neuronal activity. The level of norepinephrine (NE) was detected by HPLC-ECD. Results: Amlodipine (100mg/kg, i.g.), the well-known L-type Ca(2+) channel blockers (CCBs) exhibited remarkable antihypertensive activities in SHRs, but did not show effects on sleep of SHRs. Tetrandrine (30 and 60mg/kg/day, i.g.) significantly suppressed blood pressure of SHRs. Meanwhile, tetrandrine (60mg/kg/day, i.g.) remarkably increased non-rapid eye movement sleep (NREMS) time, bouts and mean duration. The hypnotic effect of tetrandrine was potentiated by prazosin (0.5mg/kg, i.p.) but attenuated by yohimbine (2mg/kg, i.p.). Administration of tetrandrine (60mg/kg/day, i.g.) not only significantly decreased c-Fos positive ratio of noradrenergic neurons in the locus coeruleus (LC), but also significantly decrease NE in the endogenous sleep-wake regulating pathways including LC, hypothalamus and ventrolateral preoptic nucleus (VLPO). Conclusion: In spite of a good potency in blocking L-type Ca(2+) channel, the hypnotic effects of tetrandrine may be related to its suppressing effects on the noradrenergic system other than to block calcium channels. As a multi-targets drug, tetrandrine might be favorable to the hypertension patients who suffered poor sleep.
... Many Chinese medical doctors reported that G. lucidum can improve sleep in patients with neurasthenia and mental confusion. Previous studies have shown that G. lucidum can reduce spontaneous motor activity, prolong non-rapid eye movement (NREM), and relax the central nervous system (11,12). Ganoderma lucidum can improve sleep by increasing the number of GABAA receptors (13). ...
Article
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Ganoderma resinaceum is a valuable Chinese medicine. This study aimed to investigate whether a G. resinaceum alcohol extract (GRAE) improves sleep, and analyze the potential mechanism. After 30 days of continuous administration of GRAE at various doses, GRAE (1,000 mg/kg.bw) prolonged pentobarbital sodium-induced sleep, increased the rate of sleeping in mice treated with a subthreshold dose of pentobarbital sodium, and shortened sleep latency. The mice brain was analyzed using UPLC-MS/MS and RNA-sequencing. Metabolomics analysis revealed that 73 metabolites in the high-dose (HD) group had changed significantly, mainly in amino acids and their derivatives, especially the accumulation of L-glutamine and PGJ2 (11-oxo-15S-hydroxy-prosta-5Z, 9, 13E-trien-1-oic acid). Transcriptome analysis revealed 500 differential genes between HD and control groups, mainly enriched in neuroactive ligand-receptor interaction, amphetamine addiction, and cocaine addiction pathways. The conjoint analysis of the transcriptome and metabolome showed that the biosynthesis of L-glutamine might be regulated by Homer1, Homer3 , and Grin3b . This suggests that GRAE may affect L-glutamine accumulation by regulating the expression of these genes. This study showed that GRAE may prolong the sleep time of mice by reducing the accumulation of L-glutamine and deepens our understanding of the regulatory network between certain genes and L-glutamine.
... Another five rats in each group underwent surgery 1 week prior to any PSD subjection or JTW intake, using standard procedures as bellow [25]. Under pentobarbital (50 mg/kg, intraperitoneal injection)-induced anesthesia, two stainless steel screws (2 mm long, 1.2 mm of diameter) attached to insulated wire were implanted in the skull over the frontal-parietal cortex for electroencephalographic (EEG) recordings. ...
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Background Jiao-Tai-Wan (JTW), composed of Rhizome Coptidis and Cortex Cinnamomi, is a classical traditional Chinese prescription for treating insomnia. Several in vivo studies have concluded that JTW could exert its therapeutical effect in insomnia rats. However, the specific mechanism is still unclear. The present study aimed to explore the effect of JTW on sleep in obesity-resistant (OR) rats with chronic partial sleep deprivation (PSD) and to clarify its possible mechanism. MethodsJTW was prepared and the main components contained in the granules were identified by 3D-High Performance Liquid Chromatography (3D-HPLC) assay. The Male Sprague-Dawley (SD) rats underwent 4 h PSD by environmental noise and the treatment with low and high doses of JTW orally for 4 weeks, respectively. Then sleep structure was analyzed by electroencephalographic (EEG). Inflammation markers including high-sensitivity C reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were examined in the rat plasma. Meanwhile, metabolic parameters as body weight increase rate, fasting plasma glucose (FPG), fasting insulin (FINS) levels and insulin resistance index (HOMA-IR) were measured. The expressions of clock gene cryptochromes (Cry1 and Cry2) and inflammation gene nuclear factor-κB (NF-κB) in peripheral blood monocyte cells (PBMC) were also determined. ResultsThe result showed that the administration of JTW significantly increased total sleep time and total slow wave sleep (SWS) time in OR rats with PSD. Furthermore, the treatment with JTW reversed the increase in the markers of systemic inflammation and insulin resistance caused by sleep loss. These changes were also associated with the up-regulation of Cry1 mRNA and Cry 2 mRNA and the down-regulation of NF-κB mRNA expression in PBMC. Conclusions This study suggests that JTW has the beneficial effects of improving sleep, inflammation and insulin sensitivity. The mechanism appears to be related to the modulation of circadian clock and inflammation genes expressions in PBMC.
... improve the sleeping quality. 76,77 The level and activity of SOD is one of the important indicators to measure the body recover after irradiation. Studies demonstrated that GLPS could increase the level of SOD and the numbers of leucocytes. ...
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Ganoderma lucidum is an edible medicinal mushroom known as “Lingzhi” in China and “Reishi or Manetake” in Japan. It is a highly prized vitality‐enhancing herb for more than 2000 years. G. lucidum polysaccharide (GLPS) has been identified as one of the major bioactive components and developed into a drug named “Ji 731 Injection” in China since 1973. The large‐scale production of the drug began in 1985 and approved by the Chinese FDA as “Polysaccharidum of G. lucidum Karst Injection” (Ling Bao Duo Tang Zhu She Ye) in 2000, which is applied intramuscularly. After more than forty years of clinical use, its efficacy, safety and long‐term tolerability have been recognized by neurologists. It is one of a few non‐hormonal drugs used for treating refractory myopathy. It is also used for combination therapy, which reduces the amount of glucocorticoid required for myopathy patient who is in remission. In addition, it reduces adverse reactions and improves the quality of life for cancer patients during chemotherapy. We found 81 qualified chemical, biochemical, preclinical and clinical studies of GLPS both in English and in Chinese spanning from 1973 to 2017 by searching CNKI (China National Knowledge Infrastructure), Wanfang database and PubMed. The molecular mechanisms underlying GLPS's antioxidant, anti‐tumour, immune‐modulatory, hypoglycaemic, hypolipidaemic and other activities are discussed. Both preclinical and clinical studies are either deliberated or indexed in the current article. We aimed at providing a molecular picture as well as a clinical basis to comprehend GLPS as one of few polysaccharide‐based modern medicines with complicated chemical and pharmacological properties that prevent it from entering the world's market.
... Cardiac disorders patients must take advice from consultant before use [9,176]. G. lucidum extract increases entire sleep moment with non-rapid eye movement considerably in rats with a probable mechanism linked to tumor necrosis factor-α [177]. Toxic and teratogenic effects of G. lucidum extract on zebrafish embryos have shown on dose and time dependent manner. ...
... Total sleep time was calculated as non-rapid eye movement (NREM) time plus rapid eye movement (REM) time. the details of the data parameters with four frequency ranges as follows: the delta band (0.5-4 Hz), theta band (4-8 Hz), alpha band (8-13 Hz), and beta band (13-30 Hz) (Cui et al., 2012). The data were analyzed by automatic scoring and manually checked for possible errors in the automatic scoring. ...
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Corni fructus, the fruit of Cornus officinalis Sieb. et Zucc., has been used as a tonic for the kidney in China for thousands of years. Loganin is one of the major constituents derived from Corni fructus. In this study, we revealed the sedative and hypnotic activity of loganin and investigated its mechanisms for the first time. Pentobarbital-induced sleep test and insomnia mice models [induced by caffeine and p-chlorophenylalanine (PCPA)] were used for the assessment of sedative and hypnotic effects of loganin. It was found that loganin (20–50 mg/kg) exerted sedative effect in normal mice. Loganin exhibited hypnotic effect by increasing sleep onset and sleep duration in pentobarbital-treated mice, recovering PCPA-induced insomnia and exerting synergistic hypnosis effect with 5-HTP. In addition, electroencephalograph (EEG) and electromyography (EMG) recordings of rats showed that loganin (35 mg/kg) prolonged the ratio of non-rapid eye movement (NREM) sleep and shortened wakefulness significantly, further immunohistochemistry showed that loganin (35 mg/kg) increased c-Fos expression in GABAergic neurons of rats in the ventrolateral preoptic nucleus (VLPO). The levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and its metabolite were measured in the hippocampus, prefrontal cortex and striatum of mice, 1 h after loganin (35 mg/kg) treatment. 5-HT, 5-HIAA/5-HT, DA, and DOPAC were decreased significantly in the prefrontal cortex. In conclusion, these results indicated that loganin produced beneficial sedative and hypnotic activity, which might be mainly mediated by modification of the serotonergic system and GABAergic neurons.
... Surgery and sleep analysis. At least 1 week prior to sleep recordings, the animals (9 for vehicle and 8 for CORT group) underwent surgery using previously described standard procedures 54 . Briefly, under chloral hydrate (300 mg/kg) anesthesia, two stainless steel screws attached to insulated wire were implanted in the skull over the frontal-parietal cortex for electroencephalography (EEG). ...
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Stress induced constant increase of cortisol level may lead to sleep disorder, but the mechanism remains unclear. Here we described a novel model to investigate stress mimicked sleep disorders induced by repetitive administration of corticosterone (CORT). After 7 days treatment of CORT, rats showed significant sleep disturbance, meanwhile, the glucocorticoid receptor (GR) level was notably lowered in locus coeruleus (LC). We further discovered the activation of noradrenergic neuron in LC, the suppression of GABAergic neuron in ventrolateral preoptic area (VLPO), the remarkable elevation of norepinephrine in LC, VLPO and hypothalamus, as well as increase of tyrosine hydroxylase in LC and decrease of glutamic acid decarboxylase in VLPO after CORT treatment. Microinjection of GR antagonist RU486 into LC reversed the CORT-induced sleep changes. These results suggest that GR in LC may play a key role in stress-related sleep disorders and support the hypothesis that repeated CORT treatment may decrease GR levels and induce the activation of noradrenergic neurons in LC, consequently inhibit GABAergic neurons in VLPO and result in sleep disorders. Our findings provide novel insights into the effect of stress-inducing agent CORT on sleep and GRs' role in sleep regulation.
... Cardiac disorders patients must take advice from consultant before use [9,176]. G. lucidum extract increases entire sleep moment with non-rapid eye movement considerably in rats with a probable mechanism linked to tumor necrosis factor-α [177]. Toxic and teratogenic effects of G. lucidum extract on zebrafish embryos have shown on dose and time dependent manner. ...
... In ancient China, Lingzhi was believed to be a magical medical fungus that could bring longevity through mysterious powers of healing the body and calming the mind [1]. Of interest, modern pharmacological and clinical investigations have demonstrated that G. lucidum has a numberpharmacological properties, such as anti-oxidation and delaying senescence [2], anti-diabetic effects [3,4], prolonging sleep time [5], neuroprotective effects [6], protection againstalcohol-induced liver injury [7,8], and a possible role in the treatment of cancer [9,10]. ...
Article
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In ancient China, Ganoderma lucidum was believed to be a medical fungus that could increase lifespan. Recently, pharmacologic studies have found that polysaccharide peptides and triterpenoids extracted from Ganoderma lucidum have various physiological effects as active compounds. However, the effects of spore oil isolated from Ganoderma lucidum remains unknown. In this study, the biological effects of Ganoderma lucidum spore oil (GLSO) were evaluated using a Drosophila melanogaster model. Compared with untreated groups, groups treated with GLSO had significantly longer average and maximum lifespan in both normal conditions and under oxidative stress. The activities of various antioxidant enzymes were measured to determine the antioxidant effect of GLSO. GLSO treatment markedly enhanced total superoxide dismutase (SOD) and catalase (CAT) activity and decreased levels of malondialdehyde (MDA). Further, we found dose-dependent increases in the mRNA expression of Cu, Zn-SOD, Mn-SOD, and CAT in GLSO-treated groups. These results suggest that GLSO may effectively eliminate free radicals and extend lifespan in Drosophila. Future work should investigate the value of GLSO as a functional food for the prevention of aging in larger animal models.
... Sleep problems have become a hot topic of global concern. G. lucidum has been used as a tranquilizing agent for the treatment of restlessness, insomnia, and palpitation in China for hundreds of years 26 . Chu et al. reported that 80 mg/kg and 120 mg/kg water extracts of G. lucidum prolonged the sleeping time of mice by 50% and 60%, respectively, while a 40 mg/kg dose did not significantly increased the sleeping time 13 . ...
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Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative tranquilizing effects. However, the component of G. lucidum that promotes sleep has not been clearly identified. Here, the effect and mechanism of the acidic part of the alcohol extract of G. lucidum mycelia (GLAA) on sleep were studied in mice. Administration of 25, 50 and 100 mg/kg GLAA for 28 days promoted sleep in pentobarbital-treated mice by shortening sleep latency and prolonging sleeping time. GLAA administration increased the levels of the sleep-promoting neurotransmitter 5-hydroxytryptamine and the Tph2, Iptr3 and Gng13 transcripts in the sleep-regulating serotonergic synapse pathway in the hypothalamus during this process. Moreover, GLAA administration reduced lipopolysaccharide and raised peptidoglycan levels in serum. GLAA-enriched gut bacteria and metabolites, including Bifidobacterium, Bifidobacterium animalis, indole-3-carboxylic acid and acetylphosphate were negatively correlated with sleep latency and positively correlated with sleeping time and the hypothalamus 5-hydroxytryptamine concentration. Both the GLAA sleep promotion effect and the altered faecal metabolites correlated with sleep behaviours disappeared after gut microbiota depletion with antibiotics. Our results showed that GLAA promotes sleep through a gut microbiota-dependent and serotonin-associated pathway in mice.
... Ganoderma lucidum has been used as a tranquilizing agent for the treatment of insomnia in China, which is associated with the modulation of cytokines such as TNF-α [82]; Its basidiocarp, mycelia and spores contain 400 different bioactive compounds, some of the ingredients can promoting sleep [83]. Cracked Lingzhi Spores Powder could improve the sleep function of mice [84]. ...
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Sleep is a vital segment of life, however, the mechanisms of diet promoting sleep are unclear and are the focus of research. Insomnia is a general sleep disorder and functional foods are known to play a key role in the prevention of insomnia. A number of studies have demonstrated that major insomnia risk factors in human being are less functional foods in dietary. There are higher functional components in functional foods promoting sleep, including tryptophan, GABA, calcium, potassium, melatonin, pyridoxine, L-ornithine and hexadecanoic acid; but wake-promoting neurochemical factors include serotonin, noradrenalin, acetylcholine, histamine, orexin and so on. The factors promoting sleep in human being are the functional foods include barley grass powder, whole grains, maca, panax, Lingzhi, asparagus powder, lettuce, cherry, kiwifruits, walnut, schisandra wine, and milk; Barley grass powder with higher GABA and calcium, as well as potassium is the most ideal functional food promoting sleep, however, the sleep duration for modern humans is associated with food structure of ancient humans. In this review, we put forward possible mechanisms of functional components in foods promoting sleep. Although there is clear relevance between sleep and diet, their molecular mechanisms need to be studied further.
... This may indicate that the compounds with antioxidant activity extracted from G. lucidum also elicit anti-AChE activity. The [9] for hot water extracts. ...
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Ganoderma lucidum has been used in oriental medicine for its contribution to vitality and longevity. None of them report about targeted antitumor activity against adenocarcinoma cells, or antioxidant and antiacetylcholinesterase activity for potential application in treatment of Alzheimer's and other neurodegenerative diseases. To date, there are a few studies available concerning supercritical carbon dioxide extraction of biologically active compounds from G. lucidum fruiting body. In our study, two stage extractions of biologically active compounds from G. lucidum were performed. First, supercritical carbon dioxide was used as extraction solvent. Next, the same material was used for hot water isolation of biologically active polysaccharides. Cytotoxicity, antioxidant and antiacetylcholinesterase activity were tested for all obtained extracts. Additionally, the effect of extraction process conditions on the biological activity of extracts was assessed.
... At least 1 week prior to any sleep recordings the animals were instrumented by standard procedures as reported Cui et al. (2012). Briefly, under chloral hydrate (3.5 g/kg, i.p.) anesthesia, two stainless steel screws attached to insulated wire were implanted in the skull over the frontal-parietal cortex to record the EEG. ...
... Se realizaron 2 tomas diarias de 3 gramos durante 6 semanas. (Cui, 2012-Chu, 2007-Yu, 2000 anteriormente solo en ratas (Cui, 2012-Chu, 2007-Yu, 2000-Honda, 1998, aunque no ha sido posible explicar los mecanismo de acción responsables de esta mejora. ...
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Summary of the research titled: ”Reishi (Ganoderma lucidum) effects in patients with fibromyalgia”.
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Natural products are known to play important role in pharmaceutical biology and have been important source of medicine for thousands of years. Even today, the World Health Organization (WHO) estimates that up to 80 percent of people still rely mainly on traditional medicines. As plants are one of the most important sources of medicines, a large numbers of drugs are derived such as morphine from Papaver somniferum, Aswagandha from Withania somnifera, Ephedrine from Ephedra vulgaris, Atropine from Atropa belladonna, Reserpine from Roulphia serpentina etc. These herbal plants are used as immunostimulants as an alternative to the drugs, chemicals and antibiotics currently is being used to control diseases. In this context, the use of medicinal plants and their originated products as potential therapeutic measures for modulating the immune response, biological and pharmacological activities to prevent and control diseases. The possible use of naturally available herbal plant such as Aloe vera, Urtica dioica and Zingiber officinale etc have been discussed.
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T-type calcium channel (TTCC) inhibitors hold great potential for the treatment of a variety of neurological disorders. Cochlearoids A-E (1-5), five pairs of dimeric meroterpenoid enantiomers, and cochlearines A (6) and B (7), two pairs of enantiomeric hybrid metabolites, were isolated and characterized from Ganoderma cochlear. Biological evaluation found that compounds (+)-1, (-)-3, and (±)-6 significantly inhibited Cav3.1 TTCC and showed noticeable selectivity against Cav1.2, Cav2.1, Cav2.2, and Kv11.1 (hERG) channels.
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This study was aimed to evaluate anti-inflammatory and antioxidant effect of polysaccharide peptide (PsP) from Ganoderma lucidum in atherosclerosis. The atherosclerotic rats were randomly divided into four groups (5 rats each group): atherosclerotic model with high-fat diet, low dose PsP treated group (50 mg/kgBW), medium dose PsP treated group (150 mg/kgBW), high dose PsP treated group (300 mg/kgBW), with normal mice used as a control group. Parameters measured were the level of MDA, SOD, IL - 6, IL - 10, hsCRP, TNF - á, lipid profile and foam cell. After PsP therapy for 5 weeks, the levels of MDA (p=0.01), hsCRP (p=0.018) in rats model of atherosclerosis decrease significantly. PsP can reduce levels of IL - 6 (p=0.933) and increase levels of SOD (p=0.28) descriptively at PsP doses 150 mg/kgBW. While the levels of TNF-á (p=0.894) and IL-10 (p=0.98) was not affected by administration of PsP. PsP improve the lipid profile by increasing HDL (p=0.002) and lowering total cholesterol (p=0.04). The formation of foam cells (p=0.024) as a marker of atherogenesis significantly decreased by administration of PsP. PSP can be useful to reduce inflammatory processes and oxidative stress to prevent atherogenesis.
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The main pharmacological actions of sedative agents are that they have effects of sedation, hypnosis, antianxiety, antidepression. Traditional Chinese medicine (TCM) has long clinical experience in treating insomnia. This review mainly focuses on the role of active ingredients from TCM in the treatment of insomnia. Single herbs and their active ingredients from TCM with hypnotic effect are summarized through reviewing the relevant literatures published in the past twenty years. The active ingredients are divided into alkaloids, terpenoids and volatile oils, flavonoids, lignanoids and coumarins, saponins and others. Current studies on TCM in treating insomnia are described from the aspects of active ingredients, sources, experimental model and method, result and mechanisms. In addition, Chinese compound prescriptions developed from a variety of single herbs with sedative-hypnotic effects are introduced. The acting pathways of TCM are covered from the perspectives of regulating central neurotransmitters, influencing sleep-related cytokines, improving the structure of central nervous. It is concluded that TCM is a good choice for insomnia patients for its therapeutic effect.
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Decision making on behalf of an incapacitated patient at the end of life is a complex process, particularly in family-centric societies. The situation is more complex when attempts are made to accommodate Eastern concepts of end-of-life care with more conventional Western approaches. In this case report of an incapacitated 74-year-old Singaporean man of Malay descent with relapsed Stage 4 diffuse large B cell lymphoma (DLBCL) who was without an established lasting power of attorney, we highlight the difficult deliberations that ensue when the patient's family, acting as his proxy, elected to administer Lingzhi through his nasogastric tube (NGT). Focusing upon the questions pertaining to end-of-life decision making in Asia, we consider the issues surrounding the use of NGT and zhi in palliative care (PC) and the implementation of NGT for administering Lingzhi in a PC setting, particularly in light of a dearth of data on such treatment measures among PC patients.
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Ganoderma lucidum, commonly treated as Lingzhi mushroom, is a traditional Chinese medicine which has been widely used over two millennia in Asian countries for maintaining vivacity and longevity. Numerous publications can be found reporting that G. lucidum may possess various beneficial medical properties and contributes to a variety of biological actions by primary metabolites, such as polysaccharides, proteins and triterpenes. Although G. lucidum still remains as a popular agent in commercial products, there is a lack of scientific study on the safety and effectiveness of G. lucidum in humans. There have been some reports of human trials using G. lucidum as a direct control agent for various diseases including arthritis, asthma, diabetes, gastritis, hepatitis, hypertension and neurasthenia, but scientific evidence is still inconclusive. In this paper, we discuss various aspects pertaining to the beneficial medical properties of G. lucidum (excluding anti-cancer activities). In particular, we have addressed some of the loopholes in previous studies that support G. lucidum and its secondary metabolites as effective agents to treat various human diseases. Most of the clinical trials were successful with G. lucidum preparation, however factors like small sample size, lack of a placebo control group, lack of information regarding long term treatment of the drug, age, patient's gender and side effects, standard method of extraction of G. lucidum, standard dosage, and number of patients treated undermine the validity of the results. Hence, G. lucidum can be used as a therapeutic drug when more direct and supportive scientific evidence are available in near future.
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Ganoderma lucidum is a legendary Traditional Chinese Medicine (TCM) over a few thousands of years and one kind of its major active components are Ganoderic acids (GAs). GAs are largely produced in the mushroom primordium and fruiting body but much less in mycelium stage. However, little is known on the underlying regulatory mechanism. As a saprophytic fungus, G. lucidum solely obtains nutrients by wood decaying. Wood in general contains sophisticated chemical components with diverse structural units. To explore a strategy that extensively leads to GAs induction in the submerged liquid fermentation, all chemical components that might be possibly from the wood decaying were tested individually as GAs inducers. It was found that GAs production increased 85.96% by 1.5% microcrystalline cellulose (MCC) and 63.90% by 0.5% D-galactose. The transcription level of a few rate-limiting or chemically diverting enzymes responsible for GAs biosynthesis was greatly induced by MCC and D-galactose. The concentration and time-course titration study indicated that these two chemicals might not be utilized as carbon sources but they played a comprehensive role in the secondary metabolites synthesis. Our data indicated that MCC and D-galactose might be further industrialized for higher GAs production in G. lucidum in submerged fermentation.
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Theacrine (l,3,7,9-tetramethyluric acid), a purine alkaloid from Camellia assamica var. kucha, has diverse pharmacological properties, including sedative and hypnotic activities, anti-inflammatory and analgesic activities, antidepressant effects, and a protective effect against stress-provoked liver damage. The present study aims to investigate the possible mechanism of the hypnotic activity of theacrine. The results revealed that theacrine significantly enhanced pentobarbital-induced sleep at a dose of 3.0mg/kg (i.g.) in mice. Sleep parameter analysis by EEG and EMG showed that theacrine obviously shortened wake time and increased NREM sleep time and that theacrine almost had no effect on REM sleep. Meanwhile, theacrine markedly attenuated caffeine (a nonselective antagonist of adenosine receptor)-induced insomnia. In pretreatment with the adenosine A1 receptor antagonist DPCPX and the A2A receptor antagonist SCH 58261, theacrine significantly reversed the decrease in sleeping time in pentobarbital-treated mice. In addition, theacrine also markedly increased the adenosine content in the hippocampus of rats. These results suggested that theacrine might mediate the adenosine system to augment pentobarbital-induced sleep.
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Purpose: To determine the effectiveness of adding Ganoderma lucidum (GL) to standard care for patients with fibromyalgia (FM), and to examine the costs per quality-adjusted life year (QALY) gained from this nutritional supplementation. Materials and methods: This was a randomised controlled trial with a random allocation of participants to two groups; experimental group and active-placebo controlled group. A total of 26 women with FM participated in the experimental group. These participants were instructed to take 3 g of micromilled GL twice a day for six weeks. EQ-5D-5L was used to obtain the utilities and a non-parametric bootstrap was used to plot the acceptability curve. Results: Of the women initially recruited, over 81% completed the experimental treatment. The incremental QALY in the GL group was 0.177, and the incremental QALY in the active placebo group was 0.101. Therefore, the difference in terms of QALYs was 0.076 and the incremental cost-utility ratio was €1348.55/QALYs. The cost-utility acceptability curve showed 90% probability that the addition of GL to the standard care as a nutritional supplement is cost-effective. Conclusions: The GL as nutritional supplementation in patients with FM is cost-effective in women with FM. To authors’ knowledge, the current study reports the first cost-utility analysis of GL as a nutritional supplement.
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Insomnia is one of the most troubling sleep disorders and can be characterized by an inability to fall asleep and/or inadequate sleep duration and/or waking up multiple times during the night. Herbal medicine has been used to treat a range of sleep disorders for centuries. This study aimed to review medicinal plants investigated experimentally or clinically for sleep disorders, as well as their potential mechanisms of action and active components. Electronic databases and literature were systematically investigated to assess all in vitro and in vivo trials and clinical evidence of the efficacy and potential mechanisms of actions playing major roles in sleep induction or insomnia treatment. Among many herbal studies and trials on insomnia, some showed no significant difference between herbal remedies and placebos. While others showed improvements in sleep parameters (sleep latency, total sleep, non-rapid eye movement (NREM) and rapid eye movement (REM) sleep duration, delta activity in NREM sleep, wakefulness anxiety-associated insomnia). In this study, in vitro, animal, and clinical studies investigating a variety of herbal treatments for insomnia were systematically reviewed. The mechanisms of action of herbal medicines in treating insomnia are mainly related to gamma-aminobutyric acid (GABA)-synthesizing and GABA-metabolizing enzymes that influenced sleep outcomes. Overall, herbal remedies were not associated with more benefits than non-benzodiazepines, although side effects were less. The results suggest that herbs have some benefits in improving the quantity and quality of sleep and could be a promising alternative therapy. [GMJ.2019;In press:e1085]
Chapter
Ganoderma lucidum (G. lucidum, Lingzhi) is a well-known Chinese traditional medicine to improve health and to treat numerous diseases for over 2000 years in Asian countries. G. lucidum has the abundant chemical components such as triterpenes and polysaccharides, which have various biological activities including anti-oxidation, anti-inflammation, anti-liver disorders, anti-tumor growth and metastasis, etc. Recently, many lines of studies have elucidated the therapeutic effects of G. lucidum and its extractions on various acute kidney injury (AKI) and chronic kidney disease (CKD) pathogenesis, including autosomal dominant polycystic kidney disease, diabetic nephropathy, renal proximal tubular cell oxidative damage and fibrotic process, renal ischemia reperfusion injury, cisplatin-induced renal injury, adriamycin-induced nephropathy, chronic proteinuric renal diseases, etc. Clinical researches also showed potent anti-renal disease bioactivities of G. lucidum. In this chapter, we review experimental and clinical researches and provide comprehensive insights into the renoprotective effects of G. lucidum. In recent years, renal diseases have gradually aroused attention on account of their booming prevalence worldwide and lack of effective therapies. Although the complicated pathogenesis of kidney diseases, such as acute kidney injury (AKI) and chronic kidney diseases (CKD) have been intensively studied. The morbidity and mortality of AKI and CKD still rise continuously. Thanks to the conventional experience and the multi-target characteristics, natural products have been increasingly recognized as an alternative source for treating renal diseases.
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Ganoderma lucidum (G. lucidum, Lingzhi) is a kind of medical mushroom with various pharmacological compounds. It has been used for clinical applications for thousands of years as a highly nutritious and significantly effective medicinal herb. Compared with its immunomodulatory effect, there are a few studies on the neuropharmacological actions of Ganoderma, and the mechanism has not been fully elucidated. As far as we know, Ganoderma regulate the central nervous system (CNS) at least in part through its immunomodulatory activity. The neuropharmacological effects of G. lucidum mainly include but not limited to sedative and hypnotic, neuroprotective, antinociceptive and analgesic, antiepileptic, and antidepressant effects. Clinical trials of G. lucidum in the patients with these disorders are still rare. To date, there are no Ganoderma-related drugs approved by the US Food and Drug Administration (FDA). In this chapter, we will summarize and elucidate recent progress of such effects of Ganoderma and its ingredients from both the preclinical and clinical points of view.
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In this study, an obese mouse model was developed by administering a high sugar and fat diet for 60 days, followed by administration of a special dietary supplement of Ganoderma lucidum extract for another 35 days. Then, the changes in histopathology of the liver, adipose, colon, intestines, spleen, renal and brain tissues; metabolism and transcription; and gut microbiota were monitored. The results showed that alcohol extracts of the G. lucidum fruit body could reduce body weight; change the serum levels of lipid; ameliorate the damage to the gut microbiota, colon, liver, brain and other organs induced by the high sugar and fat diet; and activate the leptin regulatory pathways in the hypothalamus to improve metabolism. These findings indicate that administration of the alcohol extracts of the G. lucidum fruit body has beneficial effects on the microbiome-gut-liver and microbiome-gut-brain axes, and activates leptin-mediated signaling to improve metabolic regulation.
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Ganoderma lucidum (Lingzhi) polysaccharide peptide (GL-pp) is a component of the globally acknowledged traditional Chinese medicine Ganoderma lucidum; Ganoderma lucidum is known for its sedative, hypnotic, immune regulatory, antitumor, and other pharmacological effects. In recent years, sleep disorders have been linked to many diseases and human body disorders, including cancer. Some experimental studies in mice found that sleep fragmentation could promote tumor development and progression. However, effects on GL-pp on tumor metastasis under circumstances of sleep disorders have rarely been studied. Thus, in this study, we used mice with sleep fragmentation (SF) bearing B16-F10-luc-G5 melanoma tumors to investigate the effect of SF on melanoma metastasis. Furthermore, we investigated the antitumor and antimetastatic effects of GL-pp (80 mg/kg) in mice suffering from SF and bearing B16-F10-luc-G5. Then, whole proteomics was used to analyze the differences in protein expression in the lung tissue between SF mice bearing B16-F10-luc-G5 with and without GL-pp administration. High-throughput pyrosequencing of 16S rRNA was also used to analyze the impact of GL-pp on the gut microbiota composition in SF mice bearing B16-F10-luc-G5. Last, the effects of GL-pp on macrophage polarization and TNF-α serum levels were detected. Collectively, we found that SF significantly facilitated the B16-F10-luc-G5 melanoma tumor metastasis in mice, while GL-pp significantly reduced B16-F10-luc-G5 melanoma tumor metastasis under the condition of SF, in which proteomics and gut microbiota had been changed greatly.
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Insomnia is one of the most troubling sleep disorders and can be characterized by an inability to fall asleep and/or inadequate sleep duration and/or waking up multiple times during the night. Herbal medicine has been used to treat a range of sleep disorders for centuries. This study aimed to review medicinal plants investigated experimentally or clinically for sleep disorders, as well as their potential mechanisms of action and active components. Electronic databases and literature were systematically investigated to assess all in vitro and in vivo trials and clinical evidence of the efficacy and potential mechanisms of actions playing major roles in sleep induction or insomnia treatment. Among many herbal studies and trials on insomnia, some showed no significant difference between herbal remedies and placebos. While others showed improvements in sleep parameters (sleep latency, total sleep, non-rapid eye movement (NREM) and rapid eye movement (REM) sleep duration, delta activity in NREM sleep, wakefulness anxiety-associated insomnia). In this study, in vitro, animal, and clinical studies investigating a variety of herbal treatments for insomnia were systematically reviewed. The mechanisms of action of herbal medicines in treating insomnia are mainly related to gamma-aminobutyric acid (GABA)-synthesizing and GABA-metabolizing enzymes that influenced sleep outcomes. Overall, herbal remedies were not associated with more benefits than nonbenzodiazepines, although side effects were less. The results suggest that herbs have some benefits in improving the quantity and quality of sleep and could be a promising alternative therapy.
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Background Ganoderma ( Lingzhi in Chinese) has shown good clinical outcomes in the treatment of insomnia, restlessness, and palpitation. However, the mechanism by which Ganoderma ameliorates insomnia is unclear. We explored the mechanism of the anti-insomnia effect of Ganoderma using systems pharmacology from the perspective of central-peripheral multi-level interaction network analysis. Methods The active components and central active components of Ganoderma were obtained from the TCMIP and TCMSP databases, then screened to determine their pharmacokinetic properties. The potential target genes of these components were identified using the Swiss Target Prediction and TCMSP databases. The results were matched with the insomnia target genes obtained from the GeneCards, OMIM, DisGeNET, and TCMIP databases. Overlapping targets were subjected to multi-level interaction network analysis and enrichment analysis using the STRING, Metascape, and BioGPS databases. The networks analysed were protein-protein interaction (PPI), drug-component-target gene, component-target gene-organ, and target gene-extended disease; we also performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results In total, 34 sedative-hypnotic components (including 5 central active components) were identified, corresponding to 51 target genes. Multi-level interaction network analysis and enrichment analysis demonstrated that Ganoderma exerted an anti-insomnia effect via multiple central-peripheral mechanisms simultaneously, mainly by regulating cell apoptosis/survival and cytokine expression through core target genes such as TNF, CASP3, JUN, and HSP90αA1; it also affected immune regulation and apoptosis. Therefore, Ganoderma has potential as an adjuvant therapy for insomnia-related complications. Conclusion Ganoderma exerts an anti-insomnia effect via complex central-peripheral multi-level interaction networks.
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Statistical analyses based on experimental designs were applied to optimize the medium components for mycelial biomass production by Trametes hirsuta in shake flask cultivation. First, the effects of different carbon resources (glucose, sucrose, lactose, maltose, fructose, soluble starch and potato), nitrogen resources (yeast extract, peptone, (NH4)2SO4, NH4NO3, NH4Cl, peanut powder, soybean powder) and mineral elements (CaCl2, ZnSO4·7H2O, FeSO4·7H2O, MnSO4·H2O, CuSO4·7H2O) on mycelial biomass production were investigated using a univariate design. Second, a Plackett-Burman design was applied to identify the significant variables that principally influenced the mycelial biomass production, and the path of steepest ascent was pursued to approach the regions of optimal value of the significant variables. Subsequently, these significant variables were optimized using the Box-Behnken design of response surface methodology. Ultimately, the optimized medium conditions were composed of sucrose 25.65 g·L-1, MgSO4·7H2O 1.24 g·L-1, and FeSO4·7H2O 3.36 g·L-1, and the yield of mycelial biomass reached 15.45 g·L-1, which represents an approximately 1.6-fold increase above the initial yield.
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Personal experience indicates we sleep differently when sick. Data reviewed demonstrate the extent to which sleep is altered during the course of infection of host organisms by several classes of pathogens. One important unanswered question is whether or not the alterations in sleep during infection are of functional relevance. That is, does the way we sleep when sick facilitate or impede recovery? One retrospective, preclinical study suggests that sleep changes during infection are of functional relevance. Toth and colleagues [102] analyzed sleep responses of rabbits to three different microbial infections. Those rabbits that exhibited robust increases in NREM sleep were more likely to survive than those that exhibited long periods of NREM sleep suppression. These tantalizing data suggest that the precise alterations in sleep through the course of infection are important determinants of morbidity and mortality. Data from healthy subjects demonstrate a role for at least two cytokines in the regulation of spontaneous, physiologic NREM sleep. A second critical yet unanswered question is whether or not cytokines mediate infection-induced alterations in sleep. The hypothesis that cytokines mediate infection-induced alterations in sleep is logical based on observations of the impact of infection on levels of cytokines in the peripheral immune system and in the brain. No attempts have been made to intervene with cytokine systems in brain during the course of infection to determine if there is an impact on infection-induced alterations in sleep. Although substantial progress has been made in elucidating the myriad mechanisms by which cytokines regulate and modulate sleep, much remains to be determined with respect to mechanistic and functional aspects of infection-induced alterations in sleep.
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Recent studies have shown that the central nervous system (CNS) communicates with the periphery by the drainage of cerebrospinal fluid and brain interstitial fluid into blood and lymph. We hypothesized that tumor necrosis factor (TNF)-alpha would not only influence the CNS by promoting sleep but also would be directly transmitted into the peripheral immune system. Five hundred nanograms of 125I-labeled TNF-alpha were injected into the lateral ventricles of the brain of six sheep and sampled in venous blood and cervical and prescapular lymph every 30 min for 6 h. 125I-TNF-alpha was measured in lymph nodes and control fat, skin, and muscle tissues 6 h postinjection. 125I-TNF-alpha was detected in the cervical lymphatics within the first 30 min and peaked within 2-3 h. 125I-TNF-alpha counts were elevated in the nodes of the head and neck region. Polysomnographic recordings of four animals showed that TNF-alpha induced a significant increase in slow-wave sleep at postinjection hours 4 and 5. CNS TNF-alpha and its direct drainage into the lymphatic system may influence both the sleeping/waking brain and peripheral immune functions.
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Much evidence suggests that tumor necrosis factor-alpha (TNF-alpha) is involved in the regulation of physiological sleep. However, it remains unclear whether peripheral administration of TNF-alpha induces sleep in rats. Furthermore, the role of the vagus nerve in the somnogenic actions of TNF-alpha had not heretofore been studied. Four doses of TNF-alpha were administered intraperitoneally just before the onset of the dark period. The three higher doses of TNF-alpha (50, 100, and 200 microg/kg) dose dependently increased nonrapid eye movement sleep (NREMS), accompanied by increases in electroencephalogram (EEG) slow-wave activity. TNF-alpha increased EEG delta-power and decreased EEG alpha- and beta-power during the initial 3 h after injection. In vagotomized rats, the NREMS responses to 50 or 100 microg/kg of TNF-alpha were attenuated, while significant TNF-alpha-induced increases in NREMS were observed in a sham-operated group. Moreover, the vagotomized rats failed to exhibit the increase in EEG delta-power induced by TNF-alpha intraperitoneally. These results suggest that peripheral TNF-alpha can induce NREMS and vagal afferents play an important role in the effects of peripheral TNF-alpha and EEG synchronization on sleep. Intraperitoneal TNF-alpha failed to affect brain temperature at the doses tested, thereby demonstrating that TNF-alpha-induced sleep effects are, in part, independent from its effects on brain temperature. Results are consistent with the hypothesis that a cytokine network is involved in sleep regulation.
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Tumor necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha) are proinflammatory cytokines involved in host defense and pathogenesis of various diseases. In addition, there is evidence that TNF is involved in sleep. TNF and LT-alpha both bind to the tumor necrosis factor receptors (TNFR). Recently, it was shown that TNF receptor 1 (TNFR1) knockout mice (R1KO) sleep less during the light period than controls. We investigated the effect of a TNF and LT-alpha double deficiency on sleep in mice (Ligand KO) and compared their sleep with that of R1KO, TNFR2 knockout (R2KO) mice, and wild-type (WT) controls. All mice were adapted to a 12:12 h light:dark cycle and their electroencephalographs (EEG) and electromyographs (EMG) were continuously recorded during a baseline day, 6-h sleep deprivation (SD), and 18-h recovery. Ligand KO and R2KO had 15% less rapid eye movement (REM) sleep during the baseline light period due to a reduction in REM sleep episode frequency. After SD, all genotypes showed an initial increase in slow-wave activity (SWA) (EEG power density between 0.75 and 4.0 Hz) in non-REM sleep, which gradually declined in the following hours. In Ligand KO the increase was mainly caused by an increase in fast SWA (2.75-4.0 Hz), which was also increased in R2KO. In contrast, in R1KO mice the increase was limited to the slow portion of SWA (0.75-2.5 Hz). R2KO and WT mice showed increases in both frequency ranges. The sub-division into fast and slow SWA frequencies corresponds to previous electrophysiological data where the two types of slow-waves were induced by either excitatory or inhibitory stimuli. Our data suggest that in Ligand KO the SWA increase is caused by an increase in excitatory input to the cortex, whereas in R1KO this input seems to be almost absent.
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It has been discussed that serotonin (5-HT) could be involved in the effects of sleep deprivation (SD) and/or malnutrition (M) on the sleep-wake cycle. The aim of this work was to study the effects of the M, SD and its interaction on 5-HT and 5-hydroxy-indole-acetic acid (5-HIAA) contents in the dorsal raphe (DR) and the suprachiasmatic nuclei (SCN), two sleep-wake cycle regulators. Forty-eight puppets rats were obtained from mothers fed with low or normal casein diet. They were allocated in 3 groups (n=16 each): prenatal/postnatal casein malnutrition (6/6%), prenatal casein malnutrition/nutritional casein rehabilitation (6/25%) and prenatal/postnatal casein well-nourished state (25/25%). When rats were 60 days old, 24 animals were exposed to sleep deprivation by means of forced locomotion during 24 h. The remaining 24 were kept under normal conditions of sleep-wake cycle. Then, all animals were sacrificed by decapitation. DR and SCN were dissected and processed to determine the 5-HT and 5-HIAA contents by means of HPLC. It was observed that 6/6% rats showed a 5-HT increase (DR p<0.011; SCN p<0.019) as well as in SD (DR p<0.0008; SCN p<0.0009) with respect to 25/25% rats. No differences were found in 6/25% rats. Therefore, 5-HIAA decreased significantly in both nuclei in all the groups, notably in M+SD animals (DR p<0.001; SCN p<0.001). We conclude that the sleep-wake cycle disruptions produced by chronic M and SD are mediated in part by a synergistic effect on 5-HT in the DR-SCN pathway, perhaps due to a delay in the development of such brain structures.
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Ganoderma lucidum has been used for the treatment of a variety of diseases. For the first time here we report a detailed study on the mechanisms and effects of G. lucidum aqueous extract (GLE) on sleep and its sedative activity. GLE showed no effects on sleep architecture in normal rats at doses of 80 and 120 mg/kg. However, GLE significantly decreased sleep latency, increased sleeping time, non-REM sleep time and light sleep time in pentobarbital-treated rats. Suppression of locomotor activity in normal mice induced by GLE was also observed. Flumazenil, a benzodiazepine receptor antagonist, at a dose of 3.5 mg/kg showed a significant antagonistic effect on the shortening in sleep latency, increase in sleeping time, non-REM sleep time or light sleep time in pentobarbital-treated rat induced by GLE. Significant effect was also observed with GLE on delta activity during non-REM sleep and flumazenil did not block this effect. In conclusion, GLE may be a herb having benzodiazepine-like hypnotic activity at least in part.
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The involvement of tumor necrosis factor (TNF) in sleep regulation was investigated by blocking TNF using a synthetic TNF receptor fragment (TNFRF) in rabbits. Intracerebroventricular injection of 50 micrograms TNFRF decreased spontaneous non-rapid-eye-movement (NREM) sleep across the 21 h recording period. After 6 h of sleep deprivation (SD), both duration of NREM sleep and electroencephalographic (EEG) slow wave activity during NREM sleep were enhanced. TNFRF suppressed SD-enhanced NREM sleep and EEG slow wave activity. SD per se did not affect rapid-eye-movement (REM) sleep, but TNFRF treatment increased REM sleep after SD. These results are consistent with the hypothesis that TNF is involved in the regulation of physiological NREM sleep.
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Tumor necrosis factor-alpha (TNF alpha) is thought to play a physiological role in the brain. These studies were performed to determine whether a diurnal rhythm of TNF alpha exist in the rat brain. Samples were collected from hippocampus, hypothalamus, cerebral cortex, cerebellum, pons and midbrain at light onset and at 6 h intervals thereafter over a day. A TNF alpha bioassay was used to measure TNF alpha in each area. TNF alpha was highest at light onset in the hypothalamus, hippocampus and cerebral cortex. Levels at light onset were about 10-fold greater than minimal night-time levels. Changes in TNF alpha activity in other brain areas were also evident, but smaller. These results support the hypothesis that TNF alpha has physiological roles in the brain.
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Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are involved in physiologic sleep regulation. Administration of exogenous IL-1 beta or TNF-alpha induces increased non-rapid eye movement sleep (NREMS). Inhibition of IL-1 or TNF reduces spontaneous sleep. There is a diurnal rhythm of TNF-alpha mRNA and IL-1 beta mRNA in brain with highest levels occurring during peak sleep periods. Mice lacking either the TNF 55-kD receptor or the IL-1 type I receptor sleep less than do strain controls. IL-1 beta and TNF-alpha are part of a larger biochemical cascade involved in sleep regulation; other somnogenic substances in this cascade include growth hormone-releasing hormone and nitric oxide. Several additional substances are involved in inhibitory feedback mechanisms, some of which inhibit IL-1 and TNF. A major challenge to sleep research is to define how and where these molecular steps produce sleep.
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Tumor necrosis factor-alpha (TNFalpha) is involved in sleep regulation. Peripheral or central administration of TNFalpha induces non-rapid eye movement sleep (NREMS) in many species. However, the brain site responsible for TNF-enhanced NREMS remains unclear. Thus, we tested the hypothesis that the preoptic area (POA) of the anterior hypothalamus, a crucial site for sleep regulation, is involved in TNF-induced sleep responses in rats. Unilateral microinjection of TNFalpha (2, 20 and 100 ng) or a TNF receptor fragment (TNFRF; 1.25, 5.0 and 12.5 microg) into the POA was performed at dark onset and light onset, respectively. The two higher doses of TNFalpha increased NREMS and brain temperature with little effect on REMS and EEG slow wave activity. These effects were lost after the heat-treatment of TNFalpha. The two higher doses of the TNFRF decreased NREMS without affecting the other parameters measured. Combined with previous results showing diurnal variations of TNFalpha in the hypothalamus, the present data suggest that POA TNFalpha is involved, in part, in the regulation of physiological sleep.
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Sleep is posited to be a fundamental property of groups of highly interconnected neurons and regulated in part by activity-dependent sleep regulatory substances such as tumor necrosis factor alpha (TNFalpha). We show that the unilateral local application of TNFalpha onto the somatosensory cortex of rats induced state- and frequency-dependent EEG asymmetries. In contrast, the unilateral injection of a TNFalpha inhibitor, a TNFalpha soluble receptor, attenuated sleep deprivation-enhanced EEG slow wave power ipsilaterally during non-rapid eye movement sleep (NREMS) but not during REMS or waking. Results are consistent with the notion that sleep begins with state changes occurring within small groups of highly interconnected neurons and is driven in part by the local production of sleep regulating substances.
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We describe here the isolation of Reishi polysaccharides for the study of their effect on cytokine expression in mouse splenocytes. A fraction (F3) has been shown to activate the expression of IL-1, IL-6, IL-12, IFN-gamma, TNF-alpha, GM-CSF, G-CSF, and M-CSF, and from this three subfractions have been prepared where F3G1 activates IL-1, IL-12, TNF-alpha, and G-CSF, F3G2 activates all the cytokines as F3 does, and F3G3 activates only IL-1 and TNF-alpha. Together with previous studies, the mode of action on macrophages has been proposed where F3 binds to TLR4 receptor and activates extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 to induce IL-1 expression.
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Ganopoly is an aqueous polysaccharide fraction extracted from G. lucidum by patented biochemical technique and has been marketed as an over-the-counter product for chronic diseases including cancer and hepatopathy in many Asian countries. This study was undertaken to explore the anti-tumour effect and the underlying mechanisms of Ganopoly in mice and human tumor cell lines. The maximum tolerated dose (MTD) of Ganopoly in mice was estimated to be 100 mg/kg from a pilot study. Treatment of mice with oral Ganopoly for 10 days significantly reduced the tumour weight of sarcoma-180 in a dose-dependent manner, with inhibition rates of 32.3, 48.2 and 84.9% and growth delays of 1.5, 3.5, and 13.1 days at 20, 50, and 100 mg/kg, respectively. Incubation of Ganopoly at 0.05-1.0 mg/ml for 48 hours showed little or negligible cytotoxicity against human tumor CaSki, SiHa, Hep3B, HepG2, HCT116 HT29, and MCF7 cells in vitro. In contrast, 10 mg/ml of Ganopoly caused significant cytotoxicity in all tumour cells tested except MCF7, with marked apoptotic effect observed in CaSki, HepG2, and HCT116 cells, as indicated by nuclear staining and DNA fragmentation. In addition, Ganopoly enhanced concanavalin A-stimulated proliferation of murine splenocytes by 35.3% at 10 mg/ml, and stimulated the production of nitric oxide in thioglycollate-primed murine peritoneal macrophages in a concentration-dependent manner over 0.05-10 mg/ml. Addition of Ganopoly at 1 mg/ ml to murine peritoneal macrophages also potentiated lipopolysaccharide-induced nitric oxide production by 64.2%. Treatment of healthy mice or mice bearing sarsoma-180 with oral Ganopoly over 20-100 mg/kg for 7 day significantly increased the expression of both TNF-alpha and IFN-gamma (at both mRNA and protein levels) in splenocytes in a dose-dependent manner. Moreover, treatment of Ganopoly over 20-100 mg/kg significantly increased cytotoxic T lymphocyte cytotoxicity and NK activity in mice. The overall findings indicated that Ganopoly had antitumor activity with a broad spectrum of immuno-modulating activities and may represent a novel promising immunotherapeutic agent in cancer treatment.
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Personal experience and empirical data indicate sleep is altered during sickness. Important signaling molecules of the peripheral immune system called cytokines orchestrate responses to infection. Through a variety of mechanisms, the brain detects activation of the peripheral immune system. The brain responds to infection by altering physiological processes and complex behavior, including sleep. These changes in physiology and behavior collectively function to support the immune system, and under normal circumstances the health of the host is restored. Several of these cytokines, and their receptors, are present in normal healthy brain. Some cytokines regulate sleep under physiological conditions, in the absence of infection or immune challenge. For example, interleukin-1 directly alters discharge patterns of neurons in hypothalamic and brainstem circuits implicated in the regulation of sleep-wake behavior. Many other cytokines modulate sleep because they interact with neurotransmitter, peptide, and/or hormone systems to initiate a cascade of responses that subsequently alter sleep-wake behavior. Because cytokines regulate/modulate sleep-wake behavior in the absence of immune challenge, and cytokine concentrations and profiles are altered during infection, it is likely that cytokines mediate infection-induced alterations in sleep. Whether the changes in sleep that occur during infection are beneficial and aid in recovery remains to be determined.
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Cytokines are mediators of immune system responses with multiple biologic actions on several target tissues. Over the past two decades, research has explored the interactions between cytokines and sleep mechanisms of the brain. This short review highlights selected findings that have advanced our understanding of the relation between cytokines and sleep. A complex network of cytokines and their receptors exists in brain. Cytokines may either promote or inhibit sleep. Of cytokines studied thus far, evidence indicates that interleukin-1 and tumor necrosis factor play a role in the regulation of non-rapid eye movement sleep. Their sites of action for regulating such sleep likely include the hypothalamic preoptic area and the basal forebrain. Mechanisms of action include direct receptor-mediated effects on neurons and the synthesis and release of numerous transmitters, peptides, and hormones that lead to subsequent changes in sleep. Among others, the cascade of responses induced by cytokines that may lead to subsequent alterations in sleep includes alterations in nitric oxide synthesis and effects on neurohormonal systems such as growth hormone releasing hormone. The activation by cytokines of the hypothalamic-pituitary-adrenal axis also influences sleep. Studies suggest that there is a significant overlap between neurohormonal systems such as the somatotropic and hypothalamic-pituitary-adrenal axes and cytokines, particularly with regard to their effects on sleep-wake regulation. There is increasing evidence of a role for cytokines in regulating spontaneous non-rapid eye movement sleep. The somatotropic hormonal system and hypothalamic-pituitary-adrenal axis mediate, in part, the effects of cytokines on sleep.
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Many herbal medicines are widely used as immuno-modulators in Asian countries. Ganoderma lucidum (Lingzhi) is one of the most commonly used herbs in Asia and preclinical studies have established that the polysaccharide fractions of G. lucidum have potent immuno-modulating effects. However, clinical evidence for this is scanty. The present open-labeled study aimed to evaluate the effects of G. lucidum polysaccharides on selected immune functions in patients with advanced colorectal cancer. Forty-seven patients were enrolled and treated with oral G. lucidum at 5.4 g/day for 12 weeks. Selected immune parameters were monitored using various immunological methods throughout the study. In 41 assessable cancer patients, treatment with G. lucidum tended to increase mitogenic reactivity to phytohemagglutinin, counts of CD3, CD4, CD8 and CD56 lymphocytes, plasma concentrations of interleukin (IL)-2, IL-6 and interferon (IFN)-gamma, and NK activity, whereas plasma concentrations of IL-1 and tumor necrosis factor (TNF)-alpha were decreased. For all of these parameters, no statistical significance was observed when a comparison was conducted between baseline and those values after a 12-week treatment with G. lucidum. The changes of IL-1 were correlated with those for IL-6, IFN-gamma, CD3, CD4, CD8 and NK activity (p<0.05) and IL-2 changes were correlated with those for IL-6, CD8 and NK activity. The results indicate that G. lucidum may have potential immuno-modulating effect in patients with advanced colorectal cancer. Further studies are needed to explore the benefits and safety of G. lucidum in cancer patients.
Study on antitumor activity and mechanism of Ganoderma polysaccharides B. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine/Zhongguo Zhong xi yi jie he xue hui
  • Q Zhang
  • Z Lin
Zhang, Q., Lin, Z., 1999. Study on antitumor activity and mechanism of Ganoderma polysaccharides B. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine/Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban 19, 544-547.