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Life Extension Magazine February 2013

Glucose and Cancer, Reishi, Tocopherol, and Hawthorn

Ganoderol B: a potent α-glucosidase inhibitor isolated from the fruiting body of Ganoderma lucidum.

α-Glucosidase inhibitor has considerable potential as a diabetes mellitus type 2 drug because it prevents the digestion of carbohydrates. The search for the constituents reducing α-glucosidase activity led to the finding of active compounds in the fruiting body of Ganoderma lucidum. The CHCl(3) extract of the fruiting body of G. lucidum was found to show inhibitory activity on α-glucosidase in vitro. The neutral fraction, with an IC(50) of 88.7 μg/ml, had stronger inhibition than a positive control, acarbose, with an IC(50) of 336.7 μg/ml (521.5 μM). The neutral fraction was subjected to silica gel column chromatography and repeated p-HPLC to provide an active compound, (3β,24E)-lanosta-7,9(11),24-trien-3,26-diol (ganoderol B). It was found to have high α-glucosidase inhibition, with an IC(50) of 48.5 μg/ml (119.8 μM).

Phytomedicine. 2011 Sep 15;18(12):1053-5

Hypoglycemic effect and mechanism of a proteoglycan from ganoderma lucidum on streptozotocin-induced type 2 diabetic rats.

BACKGROUND AND OBJECTIVES: Diabetes mellitus inducing a leading cause of morbidity are widespread in the entire globe. The present study was to investigate the antidiabetic potency and mechanism of a proteoglycan extract, named FYGL (Fudan-Yueyang-G. lucidum), from the fruiting bodies of Ganoderma Lucidum as published recently, using streptozotocin-induced type 2 diabetic mellitus (T2DM) rats. MATERIAL AND METHODS: The T2DM model rats were treated with FYGL as well as metformin and rosiglitazone. The levels of plasma glucose and insulin were measured, and the expression and activity of the protein tyrosine phosphatase 1B (PTP1B) and the tyrosine phosphorylation level of the insulin receptor (IR) 3-subunit in the livers and skeletal muscles of the T2DM rats were analyzed by immunoprecipitation and Western blotting methods. In addition, the levels of free fatty acid and serum lipid profile were measured using commercial kits for those trailed rats. RESULTS: The decrease in fasting plasma glucose and the increase in insulin concentration dose- and time-dependently in the T2DM rats treated by FYGL, comparable with that by the clinical drugs, metformin and rosiglitazone. The levels of the PTP1B expression and activity were decreased, and the tyrosine phosphorylation level of the IR 1-subunit was increased in the skeletal muscles of the T2DM rats. Furthermore, FYGL significantly decreased the levels of free fatty acid, triglyceride, total cholesterol and low density lipoprotein-cholesterol as well as increased the level of high density lipoprotein-cholesterol. DISCUSSION: It is suggested that the hypoglycemic mechanisms of FYGL are caused by inhibition of the PTP1B expression and activity, consequently, regulation of the tyrosine phosphorylation level of the IR 13-subunit. As those results, FYGL also controlled the plasma biochemistry indexes relative to the type 2 diabetes-accompanied metabolic disorders. This is possibly the first report on the underlying mechanisms responsible for the antidiabetic effect of Ganoderma lucidum.

Eur Rev Med Pharmacol Sci.2012 Feb;16(2):166-75

Novel hypoglycemic effects of Ganoderma lucidum water-extract in obese/diabetic (+db/+db) mice.

In this study, we evaluated the pharmacological effects of Ganoderma lucidum (G. lucidum) (water-extract) (0.003, 0.03 and 0.3g/kg, 4-week oral gavage) consumption using the lean (+db/+m) and the obese/diabetic (+db/+db) mice. Different physiological parameters (plasma glucose and insulin levels, lipoproteins-cholesterol levels, phosphoenolpyruvate carboxykinase (PEPCK), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) and isolated aorta relaxation of both species were measured and compared. G. lucidum (0.03 and 0.3g/kg) lowered the serum glucose level in +db/+db mice after the first week of treatment whereas a reduction was observed in +db/+m mice only fed with 0.3g/kg of G. lucidum at the fourth week. A higher hepatic PEPCK gene expression was found in +db/+db mice. G. lucidum (0.03 and 0.3g/kg) markedly reduced the PEPCK expression in +db/+db mice whereas the expression of PEPCK was attenuated in +db/+m mice (0.3g/kg G. lucidum). HMG CoA reductase protein expression (in both hepatic and extra-hepatic organs) and the serum insulin level were not altered by G. lucidum. These data demonstrate that G. lucidum consumption can provide beneficial effects in treating type 2 diabetes mellitus (T2DM) by lowering the serum glucose levels through the suppression of the hepatic PEPCK gene expression.

Phytomedicine.2009 May;16(5):426-36

Selective cholinesterase inhibition by lanostane triterpenes from fruiting bodies of Ganoderma lucidum.

Two new lanostane triterpenes, named methyl ganoderate A acetonide (1) and n-butyl ganoderate H (2), were isolated from the fruiting bodies of Ganoderma lucidum together with 16 known compounds (3-18). Extensive spectroscopic and chemical studies established the structures of these compounds as methyl 7β,15α-isopropylidenedioxy-3,11,23-trioxo-5α-lanost-8-en-26-oate (1) and n-butyl 12β-acetoxy-3β-hydroxy-7,11,15,23-tetraoxo-5α-lanost-8-en-26-oate (2). Because new compounds exhibiting specific anti-acetylcholinesterase activity are being sought as possible drug candidates for the treatment of Alzheimer's and related neurodegenerative diseases, compounds 1-18 were examined for their inhibitory activities against acetylcholinesterase and butyrylcholinesterase. All of the compounds exhibited moderate acetylcholinesterase-inhibitory activity, with IC(50) values ranging from 9.40 to 31.03μM. In contrast, none of the compounds except lucidadiol (13) and lucidenic acid N (14) exhibited butyrylcholinesterase-inhibitory activity at concentrations up to 200μM. These results indicate that these lanostane triterpenes are preferential inhibitors of acetylcholinesterase and may be suitable drug candidates.

Bioorg Med Chem Lett.2011 Nov 1;21(21):6603-7

Inhibitory effects of the methanol extract of Ganoderma lucidum on mosquito allergy-induced itch-associated responses in mice.

Recently, we showed that a methanol extract of Ganoderma lucidum inhibits scratching, an itch-related response, induced by intradermal injections of some pruritogens in mice. The present study investigated whether G. lucidum extract would inhibit allergic itch. In mice sensitized with an extract of salivary gland of mosquito (ESGM), an intradermal injection of ESGM elicited scratching, which was suppressed by oral administration of G. lucidum extract (100 and 300 mg/kg). The scratching was inhibited by the H₁ histamine-receptor antagonist azelastine, but not by the peripherally acting H₁-antagonist terfenadine, at the oral dose of 30 mg/kg. In sensitized mice, ESGM increased the activity of cutaneous nerve, which was suppressed by G. lucidum extract (300 mg/kg). Although terfenadine (30 mg/kg) inhibited plasma extravasation induced by ESGM in the sensitized mice, G. lucidum extract (300 mg/kg) was without effect. These results suggest that G. lucidum extract relieves allergic itch through a peripheral action. The results support the idea that mast cells and H₁ histamine receptors are not the primary sites of the antipruritic action of G. lucidum extract.

J Pharmacol Sci.2010;114(3):292-7

Ganoderma lucidum polysaccharides attenuate endotoxin-induced intercellular cell adhesion molecule-1 expression in cultured smooth muscle cells and in the neointima in mice.

The expression of adhesion molecules on vessels and subsequent leukocyte recruitment are critical events in vascular diseases and inflammation. The aim of the present study was to examine the effects of an extract of Ganoderma lucidum (Reishi) polysaccharides (EORP), which is effective against cancer and immunological disorders, on adhesion molecule expression by human aortic smooth muscle cells (HASMCs) and the underlying mechanism. EORP significantly suppressed lipopolysaccharide (LPS)-induced intercellular cell adhesion molecule-1 (ICAM-1) mRNA and protein expression and reduced the binding of human monocytes to LPS-stimulated HASMCs. Immunoprecipitation and real-time polymerase chain reaction demonstrated that EORP markedly reduced the interaction of human antigen R protein (HuR) with the 3'-UTR of ICAM-1 mRNA in LPS-stimulated HASMCs. EORP treatment also suppressed extracellular signal-regulated kinase (ERK) phosphorylation and reduced the density of the shifted bands of nuclear factor (NF)-kappaB after LPS-induced activation. In an endothelial-denuded artery model in LPS-treated mice, daily oral administration of EORP for 2 weeks decreased neointimal hyperplasia and ICAM-1 expression in the plasma and neointima. These results provide evidence that EORP attenuates LPS-induced adhesion molecule expression and monocyte adherence and that this protective effect is mediated by decreased ERK phosphorylation and NF-kappaB activation. These findings suggest that EORP has anti-inflammatory properties and could prove useful in the prevention of vascular diseases and inflammatory responses.

J Agric Food Chem.2010 Sep 8;58(17):9563-71

Suppression of the inflammatory response by triterpenes isolated from the mushroom Ganoderma lucidum.

Ganoderma lucidum is a popular medicinal mushroom, which has been used in the Traditional Chinese medicine for the prevention or treatment of a variety of diseases. In the present study we evaluated the anti-inflammatory effects of the triterpene extract from G. lucidum (GLT) in LPS-stimulated macrophages. Here we show that GLT markedly suppressed the secretion of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and inflammatory mediator nitric oxide (NO) and prostaglandin E(2) (PGE(2)) from lipopolysaccharide (LPS)-stimulated murine RAW264.7 cells. GLT also down-regulated LPS-dependent expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in RAW264.7 cells. The anti-inflammatory effects of GLT were mediated by the inhibition of transcription factor NF-kappaB as demonstrated by decreased NF-kappaB-DNA binding activity, and the suppression of p65 phosphorylation in LPS-stimulated macrophages treated with GLT. Moreover, GLT inhibited LPS-dependent AP-1-DNA binding activity and down-regulated expression of AP-1 subunit c-Jun. In addition, GLT suppressed the activity of MAP kinases as observed by the down-regulation of LPS-induced phosphorylation of ERK1/2 and JNK but not p38. In vivo experiments clearly demonstrated that GLT also inhibited the production of TNF-alpha and IL-6 in LPS-induced endotoxemic mice. Apart from its anti-inflammatory activity, GLT suppressed cell proliferation of RAW264.7 cells through cell cycle arrest at G0/G1-G2M, which was mediated by the down-regulation of expression of cell cycle regulatory proteins cyclin D1, CDK4 and cyclin B1, respectively. In conclusion, the anti-inflammatory and anti-proliferative effects of GLT on macrophages are mediated through the inhibition of NF-kappaB and AP-1 signaling pathways.

Int Immunopharmacol.2009 Oct;9(11):1272-80

Ganoderma lucidum extracts inhibited leukemia WEHI-3 cells in BALB/c mice and promoted an immune response in vivo.

Ganoderma lucidum (G. lucidum) is a medicinal mushroom having biological effects such as immunomodulation and anti-tumor actions. In China and many other Asian countries, G. lucidum is used as a folk remedy to promote health and longevity. Although many studies have shown that G. lucidum modulates the immune system, including, for example, antigen-presenting cells, natural killer (NK) cells, and the T and B lymphocytes, the effects of G. lucidum on the WEHI-3 leukemic BALB/c mice are unclear. We attempted to determine whether G. lucidum would promote immune responses in BALB/c mice injected with WEHI-3 leukemia cells. The effects of G. lucidum on the survival rate of WEHI-3 leukemia cells injected into BALB/c mice were examined. It increased the percentages of CD3 and CD19, but decreased the percentages of Mac-3 and CD11b markers, suggesting that differentiation of the precursor of T and B cells was promoted but macrophages were inhibited. It decreased the weight of spleens as compared with control mice. It also promoted phagocytosis by macrophage from peripheral blood mononuclear cell (PBMC) and it also promoted natural killer cell activity. It decreased the percentage of leukemia cells in the spleens of mice before they were injected with WEHI-3 cells. Apparently, G. lucidum affects murine leukemia WEHI-3 cells in vivo.

Biosci Biotechnol Biochem.2009 Dec;73(12):2589-94


Postprandial hyperglycemia impairs vascular endothelial function in healthy men by inducing lipid peroxidation and increasing asymmetric dimethylarginine:arginine.

Postprandial hyperglycemia induces vascular endothelial dysfunction (VED) and increases future cardiovascular disease risk. We hypothesized that postprandial hyperglycemia would decrease vascular function in healthy men by inducing oxidative stress and proinflammatory responses and increasing asymmetric dimethylarginine:arginine (ADMA:arginine), a biomarker that is predictive of reduced NO biosynthesis. In a randomized, cross-over design, healthy men (n = 16; 21.6 ± 0.8 y) ingested glucose or fructose (75 g) after an overnight fast. Brachial artery flow-mediated dilation (FMD), plasma glucose and insulin, antioxidants, malondialdehyde (MDA), inflammatory proteins, arginine, and ADMA were measured at regular intervals during the 3-h postprandial period. Baseline FMD did not differ between trials (P > 0.05). Postprandial FMD was reduced following the ingestion of glucose only. Postprandial MDA concentrations increased to a greater extent following the ingestion of glucose compared to fructose. Plasma arginine decreased and the ratio of ADMA:arginine increased to a greater extent following the ingestion of glucose. Inflammatory cytokines and cellular adhesion molecules were unaffected by the ingestion of either sugar. Postprandial AUC(0-3 h) for FMD and MDA were inversely related (r = -0.80; P < 0.05), suggesting that hyperglycemia-induced lipid peroxidation suppresses postprandial vascular function. Collectively, these findings suggest that postprandial hyperglycemia in healthy men reduces endothelium-dependent vasodilation by increasing lipid peroxidation independent of inflammation. Postprandial alterations in arginine and ADMA:arginine also suggest that acute hyperglycemia may induce VED by decreasing NO bioavailability through an oxidative stress-dependent mechanism. Additional work is warranted to define whether inhibiting lipid peroxidation and restoring arginine metabolism would mitigate hyperglycemia-mediated decreases in vascular function.

J Nutr.2011 Nov;141(11):1961-8

γ-Tocopherol abolishes postprandial increases in plasma methylglyoxal following an oral dose of glucose in healthy, college-aged men.

Postprandial hyperglycemia contributes to the risk of cardiovascular disease in part by increasing concentrations of the reactive dicarbonyl methylglyoxal (MGO), a byproduct of glucose metabolism. Oxidative stress increases MGO formation from glucose in vitro and decreases its glutathione-dependent detoxification to lactate. We hypothesized that the antioxidant γ-tocopherol, a form of vitamin E, would decrease hyperglycemia-mediated postprandial increases in plasma MGO in healthy, normoglycemic, college-aged men. Participants (n=12 men; 22.3±1.0 years; 29.3±2.4 kg/m(2)) received an oral dose of glucose (75 g) in the fasted state prior to and following 5-day ingestion of a vitamin E supplement enriched in γ-tocopherol (500 mg/day). γ-Tocopherol supplementation increased (P<.0001) plasma γ-tocopherol from 2.22±0.32 to 7.06±0.71 μmol/l. Baseline MGO concentrations and postprandial hyperglycemic responses were unaffected by γ-tocopherol supplementation (P>.05). Postprandial MGO concentrations increased in the absence of supplemental γ-tocopherol (P<.05), but not following γ-tocopherol supplementation (P>.05). Area under the curve for plasma MGO was significantly (P<.05) smaller with the supplementation of γ-tocopherol than without (area under the curve (0-180 min), -778±1010 vs. 2277±705). Plasma concentrations of γ-carboxyethyl-hydroxychroman, reduced glutathione and markers of total antioxidant capacity increased after supplementation, and these markers and plasma γ-tocopherol were inversely correlated with plasma MGO (r=-0.48 to -0.67, P<.05). These data suggest that short-term supplementation of γ-tocopherol abolishes the oral glucose-mediated increases in postprandial MGO through its direct and indirect antioxidant properties and may reduce hyperglycemia-mediated cardiovascular disease risk.

J Nutr Biochem.2012 Mar;23(3):292-8