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1.  Medicinal mushroom Phellinus linteus as an alternative cancer therapy 
Alternative cancer treatment with nutritional/dietary supplements containing a wide variety of herbal products is on the rise in Western countries. Recent epidemiological studies have suggested that mushrooms may prevent against different types of cancers. Phellinus linteus is a well-known Oriental medicinal fungus with a variety of biological activities, including immunomodulatory or direct antitumor activities. The activity of P. linteus and its extracts is associated with the presence of polysaccharides, their peptide/protein complexes and other low molecular weight complexes. Polysaccharide fractions isolated from P. linteus were found to be related to the increased activity of immune cells such as the production of cytokines by macrophages and B-cells or the increased cytotoxic activity of natural killer cells. Moreover, P. linteus was found to modulate the expression or activity of various genes involved in cell proliferation, apoptosis, angiogenesis, invasive behavior and chemoprevention. Finally, P. linteus extracts demonstrated tumor regression in three independent case reports, suggesting that an extract from P. linteus or a dietary supplement based on the extract from P. linteus may have potential use for the alternative treatment of cancer.
PMCID: PMC3445909  PMID: 22993555
Phellinus linteus; complementary and alternative medicine; cancer
2.  Inhibition of IgE-dependent Mouse Triphasic Cutaneous Reaction by a Boiling Water Fraction Separated from Mycelium of Phellinus linteus 
Phellinus linteus, a mushroom, contains constituents that exhibit potent antitumor effects through activating immune cells. Recently, anti-inflammatory and anti-allergic properties of P. linteus extracts have also been implicated. In the present study, therefore, we separated the constituents of mycelium of P. linteus into five fractions—chloroform-soluble (CF), ethyl acetate-soluble (EA), methanol-soluble (AE), water-soluble (WA) and boiling water-soluble (BW) fractions—and examined their suppressive effects on the IgE-dependent mouse triphasic cutaneous reaction. The triphasic reaction was induced in the ear of BALB/c mice passively sensitized with anti-dinitrophenol IgE by painting with 2,4-dinitrofluorobenzene 24 h later. Ear swelling appeared triphasically with peak responses at 1 h, 24 h and 8 days after the challenge. ME, WA and BW given orally at a dose of 100 mg kg−1 significantly inhibited the first and second phase ear swelling, and BW also inhibited the third phase response. CF only inhibited the second phase. The inhibition by BW was the most potent and almost dose-dependent at doses of 30–300 mg kg−1. BW also inhibited vascular permeability increase caused by passive cutaneous anaphylaxis and histamine, and ear swelling caused by tumor necrosis factor-α. In contrast, BW apparently potentiated the production of interleukin-4 and interferon-γ from anti-CD3-stimulated mouse splenocytes. These results indicate that BW derived from mycelium of P. linteus contains some constituents with anti-allergic as well as immunopotentiating properties.
PMCID: PMC1193546  PMID: 16136215
allergic reaction; boiling; IgE; mouse; mycelium; Phellinus linteus; water fraction
3.  Phellinus linteus Extract Exerts Anti-asthmatic Effects by Suppressing NF-κB and p38 MAPK Activity in an OVA-induced Mouse Model of Asthma 
Immune Network  2014;14(2):107-115.
Phellinus linteus has been used as a traditional herbal medicine in Asian countries and is known to have anti-tumor, immunomodulatory, anti-inflammatory, and anti-allergic activities. However, the protective effects of P. linteus against experimental asthma have not been fully investigated. The objective of this study was to determine whether P. linteus ethanol extract (PLE) suppresses inflammatory response in an OVA-induced asthma model. As expected, the oral administration of PLE significantly inhibited eosinophilic airway inflammation and airway hyperresponsiveness in OVA-challenged BALB/c mice. Supporting these data, the augmentation of Th2 cytokines (IL-4, IL-5, and IL-13), eotaxin, and adhesion molecules in lung tissues and bronchoalveolar lavage fluid after OVA inhalation was markedly attenuated by PLE. Furthermore, PLE reduced OVA-induced activation of NF-κB and p38 MAPK in lung tissues. Therefore, our results suggest the potential of P. linteus as a therapeutic agent for asthma.
PMCID: PMC4022778  PMID: 24851100
Phellinus linteus; Asthma; Allergic inflammation; Th2 cytokine; NF-κB; p38
4.  Phellinus linteus polysaccharide extracts increase the mitochondrial membrane potential and cause apoptotic death of THP-1 monocytes 
Chinese Medicine  2013;8:25.
The differentiation resp. death of human monocytic THP-1 cells induced by polysaccharide extracts of the medicinal mushrooms Phellinus linteus, Agaricus bisporus and Agaricus brasiliensis have been studied. This study aims to identify leads for the causal effects of these mushroom components on cell differentiation and death.
THP-1 cells were treated with different polysaccharide extracts of mushrooms and controls. Morphological effects were observed by light microscopy. Flow cytometry was applied to follow the cell differentiation by cell cycle shifts after staining with propidium iodide, changes of mitochondrial membrane potential after incubation with JC-1, and occurrence of intracellular reactive oxygen species after incubation with hydroethidine. Principal component analysis of the data was performed to evaluate the cellular effects of the different treatments.
P. linteus polysaccharide extracts induced dose-dependent apoptosis of THP-1 cells within 24 h, while A. bisporus and A. brasiliensis polysaccharide extracts caused differentiation into macrophages. A pure P. linteus polysaccharide had no effect. Apoptosis was inhibited by preincubating THP-1 cells with human serum. The principal component analysis revealed that P. linteus, A. bisporus and A. brasiliensis polysaccharide extracts increased reactive oxygen species production. Both A. bisporus and A. brasiliensis polysaccharide extracts decreased the mitochondrial membrane potential, while this was increased by P. linteus polysaccharide extracts.
P. linteus polysaccharide extracts caused apoptosis of THP-1 monocytes while A. bisporus and A. brasiliensis polysaccharide extracts caused these cells to differentiate into macrophages. The protective effects of human serum suggested that P. linteus polysaccharide extract induced apoptosis by extrinsic pathway, i.e. by binding to the TRAIL receptor. The mitochondrial membrane potential together with reactive oxygen species seems to play an important role in cell differentiation and cell death.
PMCID: PMC3878362  PMID: 24344650
5.  Effect of Phellius linteus water extract on benign prostatic hyperplasia 
Nutrition Research and Practice  2013;7(3):172-177.
Benign prostatic hyperplasia (BPH) is one of the most common diseases among elderly men. As the old-age population is increasing recently, it is to our interest to observe the growing BPH within them. In BPH, the dihydrotestosterone (DHT) acts as promotes prostate growth. It inhibits enzyme 5α-reductase that is involved in the conversion of testosterone to the DHT activity which reduces the excessive prostate growth. Through experiments, the effects of Phellius linteus water extract performed on the BPH rats were induced by testosterone treatments. For 12 weeks, Sprague-Dawley rats were treated with testosterone for the induction of BPH. Rats were divided into four experimental groups: the not treated group (N), the testosterone injection and D.W treatment group (TN), the testosterone injection and Phellinus linteus treatment group (TP) and testosterone injection and finasteride treatment group (TF). Prostate weight, volume and weight ratio in the TP group and the TF group were significantly lower than the TN group. Testosterone and DHT levels in the TN group were significantly higher than that of the N group. And the TP group was significantly decreased than that of the TN group. While prostates of control rats revealed severe acinar gland atrophy and stromal proliferation; the TP and TF groups showed trophic symptoms and were lined by flattened epithelial cells, thus, the stromal proliferation is relatively low as compared to the TN group. These suggest that Phellinus linteus water extracts may be an useful remedy for treating the benign prostatic hyperplasia.
PMCID: PMC3679325  PMID: 23766877
Phellius lineteus; benign prostatic hyperplasia; acne symptoms; hair growth; dihydrotestosterone
6.  Phellinus linteus Extract Augments the Immune Response in Mitomycin C-Induced Immunodeficient Mice 
Phellinus linteus is a fungus distributed throughout Japan, Korea and China. Boiled water-soluble extracts from P. linteus (PLW) have shown anti-tumor and immunomodulatory properties in experiments done by intraperitoneal treatment, or in in vitro cell cultures. This is the first investigation on how oral administration of PLW influences immune responses. Here, we established immunodeficient mice by mitomycin C (MMC) and then researched how PLW influenced plaque-forming cell (PFC) production and populations of cytokine [interferon- (IFNγ-) and interleukin-4 (IL-4)]-producing T lymphocytes. PLW samples were administered orally for 19 days (1, 2 or 4 g/kg/day). PFC assay was followed using Jerne's method. IFN- and IL-4-producing T lymphocyte populations were measured by flow-activated cell sorter (FACS). These assays were conducted the day after the last oral administration. MMC groups were given MMC (1 mg/kg/day) intraperitoneally for 6 days with PLW administration. The number of PFC per 106 spleen cells increased significantly in the PLW (2 g/kg/day) group when compared with the MMC-control (P < 0.05) while populations of IFNγ- and IL-4-producing T lymphocytes decreased by MMC treatment. However, the PLW group tended to increase more than the MMC-control. Our results indicated that PLW augments the immune response of the spleen in MMC-induced immunodeficient mice.
PMCID: PMC2249738  PMID: 18317553
immune response; mitomycin C; Phellinus linteus
7.  Filtrate of Phellinus linteus Broth Culture Reduces Infarct Size Significantly in a Rat Model of Permanent Focal Cerebral Ischemia 
Phellinus linteus, a natural growing mushroom, has been known to exhibit anti-tumor, anti-inflammatory, anti-allergic and anti-oxidant effects. Aiming to exploit the neuroprotective effects of P. linteus, we evaluated its effects on infarct volume reduction in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion. Filtrate of P. linteus broth culture (various doses), fractionated filtrate (based on molecular weight) or control medium was administered intraperitoneally to rats before or after ischemia induction. Rats were killed at 24 h after the stroke surgery. Cortical and caudoputaminal infarct volumes were determined separately using an image analysis program following staining with 2,3,5-triphenyltetrazolium chloride. Significant cortical infarct volume reductions were found in the pre-treatment groups (30 and 60 minutes before onset of cerebral ischemia) compared with the control group, showing dose dependence. Posttreatment (30 minutes after ischemic onset) also significantly reduced cortical infarct volume. Furthermore, the higher molecular weight (≥12 000) fraction of the culture filtrate was more effective compared with the lower molecular weight fraction. The present findings suggest that P. linteus may be a new promising approach for the treatment of focal cerebral ischemia, with the additional benefit of a wide therapeutic time window since significant infarct volume reduction is obtained by administration even after the ischemic event. Our finding that the higher molecular weight fraction of the P. linteus culture filtrate demonstrated more prominent effect may provide a clue to identify the neuroprotective substances and mechanisms.
PMCID: PMC3135312  PMID: 19155273
8.  Modulation of experimental atopic dermatitis by topical application of Gami-Cheongyeul-Sodok-Eum 
Gami-Cheongyeul-Sodok-Eum (GCSE), an herbal formula of traditional Korean medicine, comprises nine herb components. GCSE has various biological activities such as anti-inflammatory, anti-bacterial and anti-viral activities. However, it is still unclear whether GCSE has any immunomodulatory effect on atopic dermatitis (AD).
GCSE was treated to primary B cells and CD4+ T cells isolated from atopic mice to compare its inhibitory effects on IgE secretion and cytokine expression. Experimental AD was established by alternative treatment of 2, 4-dinitrochlorobenzene (DNCB) and house dust mite extract to the ears of BALB/c mice. GCSE was topically applied to ears of atopic mice every day for 3 weeks. AD progression was analyzed by measuring ear thickness, serum IgE level, histological examination of ear tissue by H&E staining and cytokine profile of CD4+ T cells and CD19+ B cells by real time PCR and ELISA.
Treatment of GCSE significantly reduced IgE production and expression of AD associated pathogenic cytokines such as IL-4, IL-5, IL-10, IL-13, IL-17, TNF-α, and IFN-γ by lymphocytes isolated from AD-induced mice. Topical application of GCSE on the ears of AD-induced mice significantly reduced ear thickness, clinical score and lymphocytes infiltration to ears as compared to control group. GCSE treatment also reduced serum IgE level and the levels of major pathogenic cytokines such as IL-4, IL-5, IL-10, IL-13 and IL-17. In addition, GCSE treatment significantly increased Foxp3 expression level.
The protective effect of GCSE in experimental AD is mediated by inhibition of IgE production, by reduction in the levels of pathogenic cytokines and by induction of Foxp3, all of which are suggesting the beneficial effect of GCSE on modulating atopic dermatitis.
PMCID: PMC3832229  PMID: 24499290
Atopic dermatitis; Herbal medicine; GCSE (Gami-Cheongyeul-Sodok-Eum); Th1 & Th2 cells; B cells; IgE and Cytokines
9.  Anti-cancer Activities of Ginseng Extract Fermented with Phellinus linteus 
Mycobiology  2009;37(1):21-27.
In the present study, the anti-cancer effects of ginseng fermented with Phellinus linteus (GFPL) extract were examined through in vitro and in vivo assays. GFPL was produced by co-cultivating ginseng and Phellinus linteus together. Ginsenoside Rg3, Rh1 and Rh2 are important mediators of anti-angiogenesis and their levels in GFPL were enriched 24, 19 and 16 times, respectively, more than that of ginseng itself through the fermentation. GFPL exhibited distinct anti-cancer effects, including growth inhibition of the human lung carcinoma cell line A549, and promotion of immune activation by stimulating nitric oxide (NO) production in Raw 264.7 cells. Further evidence supporting anti-cancer effects of GFPL was its significant prolongment of the survival of B16F10 cancer cell-implanted mice. These results suggest that the GFPL may be a candidate for cancer prevention and treatment through immune activation and anti-angiogenic effects by enriching Rg3, Rh1 and Rh2.
PMCID: PMC3749450  PMID: 23983502
Antitumor activity; Ginsenoside Rg3; HUVEC; Phellinus linteus
10.  Neuraminidase Inhibitors from the Fermentation Broth of Phellinus linteus 
Mycobiology  2014;42(2):189-192.
During a search for neuraminidase inhibitors derived from medicinal fungi, we found that the fermentation broth of Phellinus linteus exhibited potent neuraminidase inhibitory activity. Through bioassay-guided fractionation, two active compounds were purified from the ethyl acetate-soluble portion of the fermentation broth of P. linteus. These structures were identified as inotilone (1) and 4-(3,4-dihydroxyphenyl)-3-buten-2-one (2) by spectroscopic methods. Compounds 1 and 2 inhibited H1N1 neuraminidase activity with IC50 values of 29.1 and 125.6 µM, respectively, in a dose-dependent manner. They also exhibited an antiviral effect in a viral cytopathic effect reduction assay using MDCK cells. These results suggest that compounds 1 and 2 from the culture broth of P. linteus would be good candidates for the prevention and therapeutic strategies towards viral infections.
PMCID: PMC4112237  PMID: 25071390
4-(3,4-Dihydroxyphenyl)-3-buten-2-one; Anti-influenza agent; Inotilone; Neuraminidase inhibitor; Phellinus linteus
11.  7,8,4′-Trihydroxyisoflavone Attenuates DNCB-Induced Atopic Dermatitis-Like Symptoms in NC/Nga Mice 
PLoS ONE  2014;9(8):e104938.
Atopic dermatitis (AD) is characterized by chronic highly pruritic and relapsing inflammatory skin lesions. Despite its growing prevalence, therapeutic treatments remain limited. Natural immune modulators from herbal extracts or derivatives may be useful for treating AD symptoms. This study examined the effect of 7,8,4′-trihydroxyisoflavone (7,8,4′-THIF), a metabolite of soy isoflavone daidzin, on AD-like symptoms. Repeated epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) was performed on the ear and dorsal skin of NC/Nga mice to induce AD-like symptoms and skin lesions, and 7,8,4′-THIF (200 and 400 nmol) or tacrolimus (100 µg) was applied topically for 3 weeks to assess their anti-pruritic effects. We found that 7,8,4′-THIF alleviated DNCB-induced AD-like symptoms as quantified by skin lesion, dermatitis score, ear thickness, and scratching behavior. Histopathological analysis demonstrated that 7,8,4′-THIF decreased DNCB-induced eosinophil and mast cell infiltration into skin lesions. We also found that 7,8,4′-THIF significantly alleviated DNCB-induced loss of water through the epidermal layer. In addition to reducing the DNCB-induced increase in serum IgE, 7,8,4′-THIF also lowered skin lesion levels of the chemokine thymus and activation regulated chemokine; Th2 cytokines interleukin (IL)-4, IL-5, and IL-13; and Th1 cytokines IL-12 and interferon-γ. These results suggest that 7,8,4′-THIF might be a potential therapeutic candidate for the treatment of atopic dermatitis.
PMCID: PMC4149428  PMID: 25170825
12.  Optimal Extraction Conditions of Anti-obesity Lipase Inhibitor from Phellinus linteus and Nutritional Characteristics of the Extracts 
Mycobiology  2010;38(1):58-61.
In an effort to develop novel mushroom-derived anti-obesity nutraceuticals, water and ethanol extracts containing the lipaseinhibitory compound from Phellinus linteus were prepared, and their nutritional components were determined. The optimal conditions for the extraction of P. linteus lipase inhibitor involved the treatment of the fruiting bodies with distilled water at 80℃ for 72 hr and 80% ethanol at 100℃ for 60 hr, respectively. The distilled water extract and ethanol extract contained 10.9% and 6.11% of crude protein, and 0.96% and 15.86% of crude fat, respectively. Additionally, the distilled water extract contained a large quantity of minerals, including 239.5 mg of K, 39.3 mg of Mg, and 39.3 mg of Na. The free amino acid content of the distilled water extracts was also higher than that of the ethanol extracts, and in particular, the distilled water extracts contained 5,139 mg of asparagine, 3,891 mg of tryptophan, 2,598 mg of alanine, and 2,066 mg of serine in 100 g of the distilled water extracts. 100 g of the distilled water and ethanol extracts were found to contain 12.31 g and 8.16 g of malic acid, respectively.
PMCID: PMC3741596  PMID: 23956626
Anti-obesity; Lipase inhibition; Nutritional characteristic; Phellinus linteus
13.  Morus alba L. suppresses the development of atopic dermatitis induced by the house dust mite in NC/Nga mice 
Morus alba, a medicinal plant in Asia, has been used traditionally to treat diabetes mellitus and hypoglycemia. However, the effects of M. alba extract (MAE) on atopic dermatitis have not been verified scientifically. We investigated the effects of MAE on atopic dermatitis through in vitro and in vivo experiments.
We evaluated the effects of MAE on the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7, as well as thymus and activation-regulated chemokine (TARC/CCL17) in HaCaT cells. In an in vivo experiment, atopic dermatitis was induced by topical application of house dust mites for four weeks, and the protective effects of MAE were investigated by measuring the severity of the skin reaction on the back and ears, the plasma levels of immunoglobulin E (IgE) and histamine, and histopathological changes in the skin on the back and ears.
MAE suppressed the production of NO and PGE2 in RAW 264.7 cells, as well as TARC in HaCaT cells, in a dose-dependent manner. MAE treatment of NC/Nga mice reduced the severity of dermatitis and the plasma levels of IgE and histamine. MAE also reduced the histological manifestations of atopic dermatitis-like skin lesions such as erosion, hyperplasia of the epidermis and dermis, and inflammatory cell infiltration in the skin on the back and ears.
Our results suggest that MAE has potent inhibitory effects on atopic dermatitis-like lesion and may be a beneficial natural resource for the treatment of atopic dermatitis.
PMCID: PMC4003291  PMID: 24755250
Atopic dermatitis; Keratinocyte; Macrophage; Morus alba; NC/Nga mouse
14.  Changes of Ginsenoside Content by Mushroom Mycelial Fermentation in Red Ginseng Extract 
Journal of Ginseng Research  2011;35(2):235-242.
To obtain microorganisms for the microbial conversion of ginsenosides in red ginseng extract (RGE), mushroom mycelia were used for the fermentation of RGE. After fermentation, total sugar contents and polyohenol contents of the RGEs fermented with various mushrooms were not a significant increase between RGE and the ferments. But uronic acid content was relatively higher in the fermented RGEs cultured with Lentus edodes (2155.6 μg/mL), Phelllinus linteus (1690.9 μg/mL) and Inonotus obliquus 26137 and 26147 (1549.5 and 1670.7 μg/mL) compared to the RGE (1307.1 μg/mL). The RGEs fermented by Ph. linteus, Cordyceps militaris, and Grifola frondosa showed particularly high levels of total ginsenosides (20018.1, 17501.6, and 16267.0 μg/mL, respectively). The ferments with C. militaris (6974.2 μg/mL), Ph. linteus (9109.2 μg/mL), and G. frondosa (7023.0 μg/mL) also showed high levels of metabolites (sum of compound K, Rh1, Rg5, Rk1, Rg3, and Rg2) compared to RGE (3615.9 μg/mL). Among four different RGE concentrations examined, a 20 brix concentration of RGE was favorable for the fermentation of Ph. linteus. Maximum biotransformation of ginsneoside metabolites (9395.5 μg/mL) was obtained after 5 days fermentation with Ph. linteus. Maximum mycelial growth of 2.6 mg/mL was achieved at 9 days, in which growth was not significantly different during 5 to 9 days fermentation. During fermentation of RGE by Ph. linteus in a 7 L fermenter, Rg3, Rg5, and Rk1 contents showed maximum concentrations after 5 days similar to flask fermentation. These results confirm that fermentation with Ph. linteus is very useful for preparing minor ginsenoside metabolites while being safe for foods.
PMCID: PMC3659518  PMID: 23717066
Red ginseng extract; Fermented red ginseng; Ginsenoside metabolites; Mushroom mycelia; Phelllinus linteus
15.  Protective effect of Phellinus linteus polysaccharide extracts against thioacetamide-induced liver fibrosis in rats: a proteomics analysis 
Chinese Medicine  2012;7:23.
The hepatoprotective potential of Phellinus linteus polysaccharide (PLP) extracts has been described. However, the molecular mechanism of PLP for the inhibition of liver fibrosis is unclear. This study aims to investigate the molecular protein signatures involved in the hepatoprotective mechanisms of PLP via a proteomics approach using a thioacetamide (TAA)-induced liver fibrosis rat model.
Male Sprague–Dawley rats were divided into three groups of six as follows: Normal group; TAA group, in which rats received TAA only; and PLP group, in which rats received PLP and TAA. Liver fibrosis was induced in the rats by repeated intraperitoneal injections of TAA at a dose of 200 mg/kg body weight twice a week for 4 weeks. PLP was given orally at a dose of 50 mg/kg body weight twice a day from the beginning of the TAA treatment until the end of the experiment. The development of liver cirrhosis was verified by histological examination. Liver proteomes were established by two-dimensional gel electrophoresis. Proteins with significantly altered expression levels were identified by matrix-assisted laser desorption/ionization-time of flight/time of flight mass spectrometry and the differentially expressed proteins were validated by immunohistochemical staining and reverse transcription polymerase chain reaction.
Histological staining showed a remarkable reduction in liver fibrosis in the rats with PLP treatment. A total of 13 differentially expressed proteins including actin, tubulin alpha-1C chain, preprohaptoglobin, hemopexin, galectin-5, glutathione S-transferase alpha-4 (GSTA4), branched chain keto acid dehydrogenase hterotetrameric E1 subunit alpha (BCKDHA), glutathione S-transferase mu (GSTmu); glyceraldehyde-3-phosphate dehydrogenase (GAPDH); thiosulfate sulfurtransferase (TFT); betaine-homocysteine S-methyltransferase 1 (BHMT1); quinoid dihydropteridine reductase (QDPR); ribonuclease UK114 were observed between the TAA and PLP groups. These proteins are involved in oxidative stress, heme and iron metabolism, cysteine metabolism, and branched-chain amino acid catabolism.
The proteomics data indicate that P. linteus may be protective against TAA-induced liver fibrosis via regulation of oxidative stress pathways, heat shock pathways, and metabolic pathways for amino acids and nucleic acids.
PMCID: PMC3536605  PMID: 23075396
16.  Identification of an anticancer compound against HT-29 cells from Phellinus linteus grown on germinated brown rice 
To isolate and identify the anticancer compound against proliferation of human colon cancer cells from ethyl acetate (EtOAC) extract of Phellinus linteus grown on germinated brown rice (PB).
EtOAC extract of PB was partitioned with n-hexane, EtOAC, and water-saturated n-butanol. Anticancer compound of n-hexane layer was isolated and identified by HPLC and NMR, respectively. Cytotoxicity against HT-29 cells was tested by SRB assay.
The n-hexane layer obtained after solvent fractionation of PB EtOAC extracts showed a potent anticancer activity against the HT-29 cell line. Atractylenolide I, a eudesmane-type sesquiterpene lactone, a major anticancer substance of PB, was isolated from the n-hexane layer by silica gel column chromatography and preparative-HPLC. This structure was elucidated by one- and two-dimensional NMR spectroscopic data. Atractylenolide I has not been reported in mushrooms or rice as of yet. The isolated compound dose-dependently inhibited the growth of HT-29 human colon cancer cells.
Atractylenolide I might contribute to the anticancer effect of PB.
PMCID: PMC3761137  PMID: 24075343
Atractylenolide I; Human colon cancer cells; NMR; Phellinus linteus; Germinated brown rice
17.  BreastDefend™ prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer 
Oncology Reports  2012;28(4):1139-1145.
We have recently demonstrated that a natural dietary supplement BreastDefend (BD), which contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin), inhibits proliferation and metastatic behavior of MDA-MB-231 invasive human breast cancer cells in vitro. In the present study, we evaluated whether BD suppresses growth and breast-to lung cancer metastasis in an orthotopic model of human breast cancer cells implanted in mice. Oral application of BD (100 mg/kg of body weight for 4 weeks) by intragastric gavage did not affect body weight or activity of liver enzymes and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. Moreover, BD significantly decreased the change in tumor volume over time compared to the control group (p=0.002). BD treatment also markedly decreased the incidence of breast-to-lung cancer metastasis from 67% (control) to 20% (BD) (p<0.05) and the number of metastases from 2.8 (0.0, 48.0) in the control group to 0.0 (0.0, 14.2) in the BD treatment group (p<0.05). Finally, anti-metastatic activity of BD in vivo was further confirmed by the downregulation of expression of PLAU (urokinase plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor-4) genes in breast tumors. In conclusion, BD may be considered as a biological therapeutic agent against invasive breast cancers.
PMCID: PMC3583511  PMID: 22842551
triple negative breast cancer cells; lung cancer metastasis; dietary supplement; urokinase plasminogen activator; C-X-C chemokine receptor-4
18.  Protein-bound polysaccharide from Phellinus linteus inhibits tumor growth, invasion, and angiogenesis and alters Wnt/β-catenin in SW480 human colon cancer cells 
BMC Cancer  2011;11:307.
Polysaccharides extracted from the Phellinus linteus (PL) mushroom are known to possess anti-tumor effects. However, the molecular mechanisms responsible for the anti-tumor properties of PL remain to be explored. Experiments were carried out to unravel the anticancer effects of PL.
The anti-cancer effects of PL were examined in SW480 colon cancer cells by evaluating cell proliferation, invasion and matrix metallo-proteinase (MMP) activity. The anti-angiogenic effects of PL were examined by assessing human umbilical vein endothelial cell (HUVEC) proliferation and capillary tube formation. The in vivo effect of PL was evaluated in an athymic nude mouse SW480 tumor engraft model.
PL (125-1000 μg/mL) significantly inhibited cell proliferation and decreased β-catenin expression in SW480 cells. Expression of cyclin D1, one of the downstream-regulated genes of β-catenin, and T-cell factor/lymphocyte enhancer binding factor (TCF/LEF) transcription activity were also significantly reduced by PL treatment. PL inhibited in vitro invasion and motility as well as the activity of MMP-9. In addition, PL treatment inhibited HUVEC proliferation and capillary tube formation. Tumor growth of SW480 cells implanted into nude mice was significantly decreased as a consequence of PL treatment, and tumor tissues from treated animals showed an increase in the apoptotic index and a decrease in β-catenin expression. Moreover, the proliferation index and microvessel density were significantly decreased.
These data suggest that PL suppresses tumor growth, invasion, and angiogenesis through the inhibition of Wnt/β-catenin signaling in certain colon cancer cells.
PMCID: PMC3154178  PMID: 21781302
19.  Mycelial Extract of Phellinus linteus Induces Cell Death in A549 Lung Cancer Cells and Elevation of Nitric Oxide in Raw 264.7 Macrophage Cells 
Mycobiology  2006;34(3):143-147.
In the present study, in order to investigate the anti-proliferative phenomenon of PLME, the effects of mycelial extract of Phellinus linteus (PLME) on the growth of human lung carcinoma cell line A549 was examined. We studied on the effects of PLME on the release of nitric oxide (NO) in mouse macrophage Raw 264.7 cells. Treatment of PLME to A549 cells resulted in the growth inhibition, morphological change and induction of apoptotic cell death in a dose-dependent manner as measured by MTT assay. We found that PLME stimulated a dose-dependent increase in NO production. These findings suggest that PLME enhances the anti-tumoral activity of macrophage and may be a potential therapeutic agent for the control of human lung carcinoma cells.
PMCID: PMC3769563  PMID: 24039488
A549; Nitric oxide; Phellinus linteus; PLME; Raw 264.7
20.  Effect of Alpinia katsumadai Hayata on House Dust Mite-Induced Atopic Dermatitis in NC/Nga Mice 
We evaluated the effects of Alpinia katsumadai Hayata (AKH, Zingiberaceae) extract on the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 cells, thymus- and-activation-regulated chemokine (TARC/CCL17) in HaCaT cells, and histamine level in HMC-1 cells. In an in vivo experiment, atopic dermatitis was induced by topical application of house dust mites for 4 weeks, and the protective effects of AKH was investigated by measuring the severity of the skin reaction on the back and ears, and plasma levels of immunoglobulin E (IgE) and histamine. AKH extract suppressed the production of NO and PGE2 in RAW 264.7 cells, TARC in HaCaT cells, and histamine in HMC-1 cells in a dose-dependent manner. In in vivo experiments, the severity of dermatitis, including erythema/hemorrhage, edema, erosion and scaling, and plasma levels of IgE, and histamine were lower in NC/Nga mice with atopic dermatitis, treated with AKH extract than in untreated mice. AKH extract reduced the histological manifestations of atopic dermatitis-like skin lesions such as erosion, hyperplasia of the epidermis and dermis, and inflammatory cell infiltration on the skin of the back and ear. These results suggest that AKH inhibits the development of house dust mite-induced atopic dermatitis in NC/Nga mice.
PMCID: PMC3467941  PMID: 23082085
21.  Therapeutic Efficacy and Immunological Response of CCL5 Antagonists in Models of Contact Skin Reaction 
PLoS ONE  2010;5(1):e8725.
Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, 44AANA47-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD) is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS) is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.
PMCID: PMC2806914  PMID: 20090949
22.  Extraction and Characteristics of Anti-obesity Lipase Inhibitor from Phellinus linteus 
Mycobiology  2010;38(1):52-57.
To develop a potent anti-obesity lipase inhibitor from mushroom, the lipase inhibitory activities of various mushroom extracts were determined. Methanol extracts from Phellinus linteus fruiting body exhibited the highest lipase inhibitory activity (72.8%). The inhibitor was maximally extracted by treatment of a P. linteus fruiting body with 80% methanol at 40℃ for 24 hr. After partial purification by systematic solvent extraction, the inhibitor was stable in the range of 40~80℃ and pH 2.0~9.0. In addition to lipase inhibitory activity, the inhibitor showed 59.4% of superoxide dismutase-like activity and 56.3% of acetylcholinesterase inhibitory activity.
PMCID: PMC3741595  PMID: 23956625
Anti-obesity; Lipase inhibitor; Phellinus linteus
23.  Phellinus linteus suppresses growth, angiogenesis and invasive behaviour of breast cancer cells through the inhibition of AKT signalling 
British Journal of Cancer  2008;98(8):1348-1356.
The antitumour activity of a medicinal mushroom Phellinus linteus (PL), through the stimulation of immune system or the induction of apoptosis, has been recently described. However, the molecular mechanisms responsible for the inhibition of invasive behaviour of cancer cells remain to be addressed. In the present study, we demonstrate that PL inhibits proliferation (anchorage-dependent growth) as well as colony formation (anchorage-independent growth) of highly invasive human breast cancer cells. The growth inhibition of MDA-MB-231 cells is mediated by the cell cycle arrest at S phase through the upregulation of p27Kip1 expression. Phellinus linteus also suppressed invasive behaviour of MDA-MB-231 cells by the inhibition of cell adhesion, cell migration and cell invasion through the suppression of secretion of urokinase-plasminogen activator from breast cancer cells. In addition, PL markedly inhibited the early event in angiogenesis, capillary morphogenesis of the human aortic endothelial cells, through the downregulation of secretion of vascular endothelial growth factor from MDA-MB-231 cells. These effects are mediated by the inhibition of serine-threonine kinase AKT signalling, because PL suppressed phosphorylation of AKT at Thr308 and Ser473 in breast cancer cells. Taken together, our study suggests potential therapeutic effect of PL against invasive breast cancer.
PMCID: PMC2361714  PMID: 18362935
Phellinus linteus; invasiveness; angiogenesis; AKT
24.  Potent Anticancer Effects of Bioactive Mushroom Extracts (Phellinus linteus) on a Variety of Human Cancer Cells 
Although several therapeutic options are currently available for patients with various cancers, the outcomes are often disappointing and a more effective modality needs to be promptly established. We have been exploring an alternative approach using natural agents and two bioactive mushroom extracts isolated from Phellinus linteus (PL), namely PL-ES and PL-I-ES, were of our interest. As anticancer effects of similar extracts have been reported in several cancers, we investigated whether PL-ES and PL-I-ES might have such anticancer activities on a variety of human cancer cells in vitro.
Ten different types of human cancer cell lines, including three metastatic prostate, bladder, kidney, lung, breast, stomach, liver, and brain cancer cells, were employed and tested with PL-ES or PL-I-ES. Cell growth/viability, exertion of oxidative stress, and induction of apoptosis were assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay, lipid peroxidation (LPO) assay, and specific enzymatic assay, respectively.
PL-ES (100 µg/mL) exhibited potent anticancer activity, resulting in a significant (40-80%) growth reduction in all 10 cancer cells at 72 hours. PL-I-ES (100 µg/mL) was effective on only four cancer cells but its higher concentration at 250 µg/mL led to a significant (25-90%) growth reduction in seven cancer cells. LPO assays indicated that such a significant growth reduction by PL-ES (100 µg/mL) or PL-I-ES (100 or 250 µg/mL) could result from cell death due to a cytotoxic effect of oxidative stress (through free radicals). Moreover, enzymatic assays for caspase-3 (Csp-3) and caspase-9 (Csp-9), the pro-apoptotic regulators, showed that both enzymes were significantly activated by PL-ES or PL-I-ES, indicating that cell death due to oxidative stress was more likely associated with apoptosis.
The present study shows that both PL-ES and PL-I-ES indeed have anticancer effects on a variety of cancer cells, although PL-ES appears to be more potent than PL-I-ES. Such an anticancer effect is presumably attributed to oxidative stress, which will ultimately lead to apoptosis. Therefore, these two bioactive mushroom extracts may have clinical implications in a more effective therapeutic option for a variety of human malignancies.
PMCID: PMC4245057  PMID: 25436023
Anticancer; Mushroom; PL-fractions; Apoptosis; Human cancer cells
25.  Therapy of atopic eczema 
Major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany.
This health technology assessment (HTA) evaluates systemically randomized controlled studies (RCT) on the therapy of atopic dermatitis which were published between 1999 and 2004. Further it includes some important clinical studies which have been published after 2004 and other updates the English HTA report by Hoare et al. [1].
Topical corticosteroids and topical calcineurin-inhibitors are the principal substances which are currently used for anti-inflammatory therapy in atopic dermatitis. These substances have shown a significant therapeutic efficacy in controlled studies. In newer controlled studies no difference was observable when corticosteroids were applied once or more than once daily onto the skin. Moreover, there is now one controlled study available which points to the fact that an interval therapy with a stronger topical corticosteroid over a limited time (some weeks) may lower the risk of recurrent flares of atopic dermatitis. Both topical calcineurin-inhibitors pimecrolimus and tacrolimus have shown a significant therapeutical efficacy in a number of placebo-controlled prospective studies. The wealth of data is high for these substances. Both substances have been shown to be efficient in infants, children and adult patients with atopic dermatitis.
The importance of a so-called basic therapy with emollients which have to be adapted to the current status of skin is generally accepted in clinical practice. Controlled studies show the efficacy of ”basic therapy” - although the level of evidence is quite low for this approach. The skin of patients with atopic dermatitis is colonized in the majority with Staphylococcus aureus, a gram-positive bacterium. Therefore, a therapeutical approach for the treatment of atopic dermatitis is the anti-bacterial or anti-septic treatment of the skin. Due to the lack of randomized controlled studies there is still not certain proof that antimicrobial or anti-septic treatment of non-infected eczematous skin is efficient for the treatment of atopic dermatitis. A reduction of Staphylococcus aureus is observable during an anti-inflammatory treatment of the skin with topical corticosteroids and/or the topical calcineurin-inhibitor tacrolimus. Antihistaminic drugs which are orally applied in atopic dermatitis may support the therapy of the itching skin disease. One controlled study showed a rapid reduction of itch during the use of a non-sedating antihistaminic drug. There are, however, no controlled studies which show the efficacy of antihistaminic drugs on the skin condition in atopic dermatitis.
Dietetic restrictions should be applied only after a specific allergological diagnostic clarification. The “gold standard” is still a (blinded) oral provocation test which has to show an influence of a given food on the skin condition. There is sufficient evidence that there is no general dietetic approach which shows efficacy in atopic dermatitis. The treatment of patients with lactobacillae is still controversially discussed. Available studies which showed an efficacy show methodological weaknesses so that this approach can not be generally recommended for clinical practice at the time now. Approaches reducing house dust mite in the surroundings of patients with atopic dermatitis can have an effect on the skin condition so that at least in mite sensitized patients this approach appears to be reasonable. The specific immunotherapy with house dust mite showed clinical efficacy in a controlled study and in some open studies. The education of patients with atopic dermatitis or their parents is a further efficient approach in the management of this chronic skin disease. Interdisciplinary approaches in patients’ education containing also psychological elements appear to be an attractive new approach for the treatment of atopic dermatitis.
Phototherapy is a further possibility of intervention in atopic dermatitis in adolescent or adult patients. The available evidence points to the fact that UVB radiation (both small and broad spectrum), UVA-1 radiation and balneo-phototherapy are efficient therapeutical options for atopic dermatitis. The systemic treatment with the immunosuppressive substance cyclosporine A is efficient in the treatment of severe atopic dermatitis. Cyclosoprine A is approved for the treatment of adult patients with this skin disease. The immunosuppressive substance azathioprine showed a high clinical efficacy in two controlled studies for severe atopic dermatitis in adults. There are still controversial results for the application of antagonists to leucotriens in the treatment of atopic dermatitis: in some open studies a therapeutical efficacy was described which was, however, not reproducible in a newer controlled study. The phosphodiesterase-4-inhibitor cipamphyllin was efficient in the treatment of atopic dermatitis in a controlled study but weaker than a topical class II (i. e. moderate strength) corticosteroide. The HTA assessment further describes so-called complementary therapeutical approaches which have either not properly been studied in controlled clinical trials or which have been shown to be of no value for the treatment of atopic dermatitis.
Altogether six full health-economic evaluations were found which did not cover the whole therapy spectrum of atopic dermatitis. The choice of the most cost effective treatment option of topic corticosteroids depends less on application frequency, but rather on the drug price and more used or unused quantity of the standard packages, so even smallest improvements justify a more frequent application. The results from health economic evaluations of calcineurin-inhibitors are not reliable. The therapy of severe atopic dermatitis in adults with ciclosporin shows comparable cost effectiveness in comparison to UVA/UVB therapy.
The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults.
The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults.
Due to lack of health economic evaluations therapy decisions in the treatment of atopic dermatitis must take place on the basis of clinical decision criteria. The prescription of topic corticosteroids should prefer low priced drugs. Reliable statements about the cost effectiveness of the new calcineurin-inhibitors tacrolimus and pimecrolimus.
PMCID: PMC3011357  PMID: 21289970

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