Life Extension Magazine®

Issue: Feb 2013

Glucose and Cancer, Reishi, Tocopherol, and Hawthorn

Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.

BACKGROUND: New diagnostic criteria for diabetes based on fasting blood glucose (FBG) level were approved by the American Diabetes Association. The impact of using FBG only has not been evaluated thoroughly. The fasting and the 2-hour glucose (2h-BG) criteria were compared with regard to the prediction of mortality. METHODS: Existing baseline data on glucose level at fasting and 2 hours after a 75-g oral glucose tolerance test from 10 prospective European cohort studies including 15,388 men and 7,126 women aged 30 to 89 years, with a median follow-up of  8.8 years, were analyzed. Hazards ratios for death from all causes, cardiovascular disease, coronary heart disease, and stroke were estimated. RESULTS: Multivariate Cox regression analyses showed that the inclusion of FBG did not add significant information on the prediction of 2h-BG alone (P>.10 for various causes), whereas the addition of 2h-BG to FBG criteria significantly improved the prediction (P<.001 for all causes and P<.005 for cardiovascular disease). In a model including FBG and 2h-BG simultaneously, hazards ratios (95% confidence intervals) in subjects with diabetes on 2h-BG were 1.73 (1.45-2.06) for all causes, 1.40 (1.02-1.92) for cardiovascular disease, 1.56 (1.03-2.36) for coronary heart disease, and 1.29 (0.66-2.54) for stroke mortality, compared with the normal 2h-BG group. Compared with the normal FBG group, the corresponding hazards ratios in subjects with diabetes on FBG were 1.21 (1.01-1.44), 1.20 (0.88-1.64), 1.09 (0.71-1.67), and 1.64 (0.88-3.07), respectively. The largest number of excess deaths was observed in subjects who had impaired glucose tolerance but normal FBG levels. CONCLUSION: The 2h-BG is a better predictor of deaths from all causes and cardiovascular disease than is FBG.

Arch Intern Med. 2001 Feb 12;161(3):397-405

Prospective study on the role of glucose metabolism in breast cancer occurrence.

High circulating glucose, insulin resistance and obesity appear to be associated with increased risk of breast cancer (BC). We sought further insight into the relation of these variables to BC. We assessed associations of BC risk with serum fasting glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) index and sex-binding hormone globulin (SHBG) in women recruited to the ORDET cohort who gave blood samples in 1987-1992. After a median 13.5 years of follow-up, 356 women developed BC. Four matched controls per case were selected by incidence density sampling, and rate ratios (RR) were estimated by conditional logistic regression. Women in the highest glucose quartile had a significantly greater risk of BC than those in the lowest glucose quartile (RR 1.63; 95% CI: 1.14-2.32; p for trend of 0.003). The association was significant in pre and post menopausal women separately and in women diagnosed after 55 years. Women in the highest HOMA-IR quartile had higher BC risk than the lowest quartile (RR 1.44; 95% CI: 1.03-2.02). Significantly increased BC risk in women diagnosed after 55 years was also present in the highest HOMA-IR quartile; in the same group decreased BC risk was significantly associated with high SHBG. The results of this study add to the existing epidemiological evidence that hyperglycemia and insulin resistance increase BC risk.

Int J Cancer.2012 Feb 15;130(4):921-9

Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer.

Experimental and epidemiological evidence suggests that circulating glucose and insulin may play a role in breast carcinogenesis. However, few cohort studies have examined breast cancer risk in association with glucose and insulin levels, and studies to date have had only baseline measurements of exposure. We conducted a longitudinal study of postmenopausal breast cancer risk using the 6% random sample of women in the Women's Health Initiative clinical trials whose fasting blood samples, provided at baseline and at years 1, 3, and 6, were analyzed for glucose and insulin. In addition, a 1% sample of women in the observational study, who had glucose and insulin measured in fasting blood samples drawn at baseline and in year 3, were included in the analysis. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for the association of baseline and follow-up measurements of serum glucose and insulin with breast cancer risk. All statistical tests were 2-sided. Among 5,450 women with baseline serum glucose and insulin values, 190 incident cases of breast cancer were ascertained over a median of 8.0 years of follow-up. The highest tertile of baseline insulin, relative to the lowest, was associated with a 2-fold increase in risk in the total population (multivariable hazard ratio 2.22, 95% confidence interval 1.39-3.53) and with a 3-fold increase in risk in women who were not enrolled in the intervention arm of any clinical trial (multivariable hazard ratio 3.15, 95% confidence interval 1.61-6.17). Glucose levels showed no association with risk. Analysis of the repeated measurements supported the results of the baseline analysis. These data suggest that elevated serum insulin levels may be a risk factor for postmenopausal breast cancer.

Int J Cancer.2009 Dec 1;125(11):2704-10

Prospective study of hyperglycemia and cancer risk.

OBJECTIVE: To investigate whether hyperglycemia is associated with increased cancer risk. RESEARCH DESIGN AND METHODS: In the Västerbotten Intervention Project of northern Sweden, fasting and postload plasma glucose concentrations were available for 33,293 women and 31,304 men and 2,478 incident cases of cancer were identified. Relative risk (RR) of cancer for levels of fasting and postload glucose was calculated with the use of Poisson models, with adjustment for age, year of recruitment, fasting time, and smoking status. Repeated measurements 10 years after baseline in almost 10,000 subjects were used to correct RRs for random error in glucose measurements. RESULTS: Total cancer risk in women increased with rising plasma levels of fasting and postload glucose, up to an RR for the top versus bottom quartile of 1.26 (95% CI 1.09-1.47) (P(trend) <0.001) and 1.31 (1.12-1.52) (P(trend) = 0.001), respectively. Correction for random error in glucose measurements increased these risks up to 1.75 (1.32-2.36) and 1.63 (1.26-2.18), respectively. For men, corresponding uncorrected RR was 1.08 (0.92-1.27) (P(trend) = 0.25) and 0.98 (0.83-1.16) (P(trend) = 0.99), respectively. Risk of cancer of the pancreas, endometrium, urinary tract, and of malignant melanoma was statistically significantly associated with high fasting glucose with RRs of 2.49 (1.23-5.45) (P(trend) = 0.006), 1.86 (1.09-3.31) (P(trend) = 0.02), 1.69 (0.95-3.16) (P(trend) = 0.049), and 2.16 (1.14-4.35) (P(trend) = 0.01), respectively. Adjustment for BMI had no material effect on risk estimates. CONCLUSIONS: The association of hyperglycemia with total cancer risk in women and in women and men combined for several cancer sites, independently of obesity, provides further evidence for an association between abnormal glucose metabolism and cancer.

Diabetes Care. 2007 Mar;30(3):561-7

Association between diabetes mellitus and breast cancer risk: a meta-analysis of the literature.

AIM/HYPOTHESIS: Diabetes and breast cancer are both serious life-threatening diseases across the world. Some studies shows that diabetes is associated with many kinds of tumor, but links with breast cancer remain controversial. The aim of this study was to assess the association the available evidence. SUBJECTS AND METHODS: A meta-analysis was conducted including 16 studies published between 2000 and 2010 and summary relative risks (RRs) with 95% CIs were calculated using random-effects model. RESULTS: The combined evidence supports that diabetes was associated with a statistically significant 23% increased risk of breast cancer, especially in postmenopausal women (RR=1.25 95%CI 1.20-1.29). The correlation between diabetes and breast cancer was the most obvious in Europe (RR=1.88,95%CI:1.56-2.25), followed by America (RR=1.16, 95%CI:1.12-1.20). In Asia the result was not significant (RR=1.01, 95%CI=0.84-1.21). Diabetes also increased mortality from breast cancer overall (RR=1.44, 95%CI:1.31-1.58). CONCLUSIONS/INTERPRETATION: This meta-analysis indicated that diabetes can be considered as a risk factor for breast cancer. In addition, menstruation status as well as geographical distribution can affect the relationship.

Asian Pac J Cancer Prev.2011;12(4):1061-5

Metabolic syndrome and breast cancer: an overview.

Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the most important cause of cancer-related deaths among women. This disease is on the rise in Turkey. Metabolic syndrome is a cluster of metabolic disturbances including insulin resistance, dyslipidemia, hypertension, abdominal obesity and high blood sugar. Several studies have examined the association of the individual components of the metabolic syndrome with breast cancer. More recent studies have shown it to be an independent risk factor for breast cancer. It has also been associated with poorer prognosis, increased incidence, a more aggressive tumor phenotype. Basic research studies are now in progress to illuminate the molecular pathways and mechanisms that are behind this correlation. Given the fact that all of the components of metabolic syndrome are modifiable risk factors, preventive measures must be established to improve the outcome of breast cancer patients. In this review we set the background by taking into account previous studies which have identified the components of metabolic syndrome individually as breast cancer risk factors. Then we present the latest findings which elaborate possible explanations regarding how metabolic syndrome as a single entity may affect breast cancer risk.

J BUON.2012 Apr-Jun;17(2):223-9.

Metabolic syndrome and breast cancer in the me-can (metabolic syndrome and cancer) project.

BACKGROUND: Few studies have assessed the metabolic syndrome (MetS) as an entity in relation to breast cancer risk, and results have been inconsistent. We aimed to examine the association between MetS factors (individually and combined) and risk of breast cancer incidence and mortality. METHODS: Two hundred ninety thousand women from Austria, Norway, and Sweden were enrolled during 1974-2005, with measurements of height, weight, blood pressure, and levels of glucose, cholesterol, and triglycerides. Relative risks (RR) of breast cancer were estimated using Cox proportional hazards regression for each MetS factor in quintiles and for standardized levels (z-scores) and for a composite z-score for the MetS. RESULTS: There were 4,862 incident cases of breast cancer and 633 deaths from breast cancer identified. In women below age 50, there was a decreased risk of incident cancer for the MetS (per 1-unit increment of z-score; RR, 0.83; 95% confidence interval, 0.76-0.90) as well as for the individual factors (except for glucose). The lowest risks were seen among the heaviest women. In women above age 60, there was an increased risk of breast cancer mortality for the MetS (RR, 1.23; 95% confidence interval, 1.04-1.45) and for blood pressure and glucose. The strongest association with mortality was seen for increased glucose concentrations. CONCLUSIONS: The MetS was associated with a decreased risk of incident breast cancer in women below age 50 with high body mass index, and with an increased risk of breast cancer mortality in women above 60. IMPACT: Lifestyle interventions as recommended for cardiovascular disease prevention may be of value to prevent breast cancer mortality in postmenopausal women.

Cancer Epidemiol Biomarkers Prev.2010 Jul;19(7):1737-45

Inflammation markers and metabolic characteristics of subjects with 1-h plasma glucose levels.

OBJECTIVE: To assess the association of 1-h plasma glucose (1hPG) and inflammation with normal glucose tolerance (NGT) and pre-diabetes. RESEARCH DESIGN AND METHODS: A cohort of 1,062 subjects was enrolled. After oral glucose load (oral glucose tolerance test), we compared subjects with NGT and pre-diabetes above and below the 1hPG cut point (155 mg/dl). Fibrinogen and leukocytes count (white blood cells [WBCs]) for subclinical inflammation, lipid ratios, insulin sensitivity (Matsuda index) were determined. RESULTS: Patients with NGT and pre-diabetes (1hPG >155 mg/dl) showed a significant increase of inflammatory markers and lipid ratios (for all, P < 0.05). In age-, sex-, and BMI-adjusted analysis, 1hPG was associated with a significantly higher WBC count and fibrinogen (P < 0.05). Patients with elevated 1hPG showed a highly significant lower insulin sensitivity than subjects <1hPG (P < 0.01). CONCLUSIONS: Elevated 1hPG in subjects with NGT and pre-diabetes is associated with subclinical inflammation, high lipid ratios, and insulin resistance. Therefore, 1hPG >155 mg/dl could be considered a new "marker" for cardiovascular risk.

Diabetes Care. 2010 Feb;33(2):411-3. Epub 2009 Nov 16

Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study.

OBJECTIVES: Substantial evidence showing an association between type 2 diabetes (T2D) and cerebral atrophy, cognitive impairment, and dementia is accumulating. However, relatively little is known about the subclinical effects of high plasma glucose levels within the normal range. The aim of this study was to investigate the association between plasma glucose levels and hippocampal and amygdalar atrophy in a sample of 266 cognitively healthy individuals free of T2D, aged 60-64 years, taking part in a longitudinal study of aging. METHODS: Fasting plasma glucose was assessed at wave 1. Hippocampal and amygdalar volumes were manually traced on 1.5 T MRI scans collected at wave 1 and at wave 24 years later. General linear model analyses were used to assess the relationship between plasma glucose and incident medial temporal lobe atrophy after controlling for a range of sociodemographic and health variables. RESULTS: Plasma glucose levels were found to be significantly associated with hippocampal and amygdalar atrophy and accounted for 6%-10% in volume change after controlling for age, sex, body mass index, hypertension, alcohol, and smoking. CONCLUSIONS: High plasma glucose levels within the normal range (<6.1 mmol/L) were associated with greater atrophy of structures relevant to aging and neurodegenerative processes, the hippocampus and amygdala. These findings suggest that even in the subclinical range and in the absence of diabetes, monitoring and management of plasma glucose levels could have an impact on cerebral health. If replicated, this finding may contribute to a reevaluation of the concept of normal blood glucose levels and the definition of diabetes.

Neurology. 2012 Sep 4;79(10):1019-26

Coffee consumption and the incidence of type 2 diabetes in men and women with normal glucose tolerance: the Strong Heart Study.

BACKGROUND AND AIMS: It was reported that high coffee consumption was related to decreased diabetes risk. The aim of this study is to examine the association between coffee consumption and the incidence of type 2 diabetes in persons with normal glucose tolerance in a population with a high incidence and prevalence of diabetes. METHODS AND RESULTS: In a prospective cohort study, information about daily coffee consumption was collected at the baseline examination (1989-1992) in a population-based sample of American Indian men and women 45-74 years of age. Participants with normal glucose tolerance (N = 1141) at the baseline examination were followed for an average of 7.6 years. The incidence of diabetes was compared across the categories of daily coffee consumption. The hazard ratios of diabetes related to coffee consumption were calculated using Cox proportional hazards models, adjusted for potential confounders. Levels of coffee consumption were positively related to levels of current smoking and inversely related to body mass index, waist circumference, female gender, and hypertension. Compared to those who did not drink coffee, participants who drank 12 or more cups of coffee daily had 67% less risk of developing diabetes during the follow-up (hazard ratio: 0.33, 95% confidence interval: 0.13, 0.81). CONCLUSION: In this population, a high level of coffee consumption was associated with a reduced risk of deterioration of glucose metabolism over an average 7.6 years of follow-up. More work is needed to understand whether there is a plausible biological mechanism for this observation.

Nutr Metab Cardiovasc Dis. 2011 Jun;21(6):418-23

Reishi

Protective effects of Ganoderma lucidum spore on cadmium hepatotoxicity in mice.

The medicinal fungus Ganoderma lucidum has been shown to have hepatoprotective effects. G. lucidum contains triterpenes and polysaccharides, and the Sporoderm-broken G. lucidum powder is particular beneficial. This study utilized G. lucidum spore to examine its effect on [Cd(II)]-induced hepatotoxicity in mice and the mechanism of the protection. Mice were pretreated with G. lucidum spore (0.1, 0.5, and 1.0g/kg, po, for 7days), and subsequently challenged with a hepatotoxic dose of Cd(II) (3.7mg/kg, ip). Liver injury was evaluated 8h later. G. lucidum spore protected against Cd(II)-induced liver injury in a dose-dependent manner, as evidenced by serum alanine aminotransferase, aspartate aminotransferase and histopathology. To examine the mechanism of protection, subcellular distribution of Cd(II) was determined. G. lucidum spore decreased Cd(II) accumulation in hepatic nuclei, mitochondria, and microsomes, but increased Cd(II) distribution to the cytosol, where Cd(II) is sequestered by metallothionein, a protein against Cd(II) toxicity. Indeed, G. lucidum spore induced hepatic metallothionein-1 mRNA 8-fold, and also increased metallothionein protein as determined by the Cd(II)/hemoglobin assay. Cd(II)-induced oxidative stress was also decreased by G. lucidum spore, as evidenced by decreased formation of malondialdehyde. In summary, G. lucidum spore is effective in protection against Cd(II)-induced hepatotoxicity, and this effect is due, at least in part, to the induction of hepatic metallothionein to achieve beneficial effects.

Food Chem Toxicol.2012 May 29

Ganoderma lucidum polysaccharide accelerates refractory wound healing by inhibition of mitochondrial oxidative stress in type 1 diabetes.

BACKGROUND/AIMS: Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens. The present study was designed to determine the protective effect of Ganoderma lucidum polysaccharide (Gl-PS) on diabetic wound healing and investigate underlying mechanisms. METHODS: Streptozotocin (STZ)-induced type 1 diabetic mice with full-thickness excisional wounds were intragastrically administered with 10, 50 or 250 mg/kg/day of Gl-PS. RESULTS: Gl-PS dose-dependently rescued the delay of wound closure in diabetic mice. 50 and 250 mg/kg/day of Gl-PS treatment significantly increased the mean perfusion rate around the wound in diabetic mice. Diabetic conditions markly increased mitochondrial superoxide anion (O(2)·(-)) production, nitrotyrosine formation, and inducible nitric oxide synthase (iNOS) activity in wound tissues, which were normalized with Gl-PS treatment. In diabetic wound tissues, the protein level of manganese superoxide dismutase (MnSOD) was unchanged whereas MnSOD activity was inhibited and its nitration was potentiated; Gl-PS administration suppressed MnSOD nitration and increased MnSOD and glutathione peroxidase (GPx) activities. Moreover, Gl-PS attenuated the redox enzyme p66Shc expression and phosphorylation dose-dependently in diabetic mice skin. CONCLUSION: Gl-PS rescued the delayed wound healing and improved wound angiogenesis in STZ-induced type 1 diabetic mice, at least in part, by suppression of cutaneous MnSOD nitration, p66Shc and mitochondrial oxidative stress.

Cell Physiol Biochem.2012;29(3-4):583-94

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

Tocopherol

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

Postprandial glucose regulation: new data and new implications.

BACKGROUND: Type 2 diabetes is characterized by a gradual decline in insulin secretion in response to nutrient loads; hence, it is primarily a disorder of postprandial glucose (PPG) regulation. However, physicians continue to rely on fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) to guide management. OBJECTIVES: The objectives of this article are to review current data on postprandial hyperglycemia and to assess whether, and how, management of type 2 diabetes should change to reflect new clinical findings. METHODS: Articles were selected from MEDLINE searches (key words: postprandial glucose, postprandial hyperglycemia, and cardiovascular disease) and from our personal reference files, with emphasis on the contribution of postprandial hyperglycemia to overall glycemic load or cardiovascular (CV) risk. RESULTS: About 33% of people diagnosed as having type 2 diabetes based on postprandial hyperglycemia have normal FPG. PPG contributes > or =70% to the total glycemic load in patients who are fairly well controlled (HbA1c <7.3%). Furthermore, there is a linear relationship between the risk of CV death and the 2-hour oral glucose tolerance test (OGTT). Increased mortality is evident at OGTT levels of approximately 90 mg/dL (5 mmol/L), which is well below current definitions of type 2 diabetes. Biphasic insulin aspart was shown to be more effective at reducing HbA1c below currently recommended levels than basal insulin glargine (66% vs 40%; P < 0.001), and it reduced endothelial dysfunction more effectively than regular insulin (P < 0.01). Repaglinide achieved regression of carotid atherosclerosis (intima-media thickness) in 52% of patients versus 18% for glyburide (P < 0.01) over 1 year, although levels of HbA1c and CV risk factors were similar for both treatment groups. Finally, acarbose reduced the relative risk of CV events by 49% over 3.3 years versus placebo in patients with impaired glucose tolerance (2.2% vs 4.7%; P = 0.03) and by 35% over > or =1 year in patients with type 2 diabetes (9.4% vs 6.1%; P = 0.006). CONCLUSIONS: All components of the glucose triad (ie, FPG, HbA1c, and PPG) should be considered in the management of type 2 diabetes. Therapy targeted at PPG has been shown to improve glucose control and to reduce the progression of atherosclerosis and CV events; therefore, physicians should consider monitoring and targeting PPG, as well as HbA1c and FPG, in patients with type 2 diabetes.

Clin Ther.2005;27 Suppl B:S42-56

Impaired glucose tolerance, but not impaired fasting glucose, underlies left ventricular diastolic dysfunction.

OBJECTIVE: Glucose intolerance is recognized as a predictor of congestive heart failure (CHF). However, the association of postprandial hyperglycemia or fasting hyperglycemia with CHF has not been clarified. We determined the impact of the total spectrum of glucose abnormalities on left ventricular (LV) geometry and diastolic function. RESEARCH DESIGN AND METHODS: Two hundred and eighty-seven Japanese subjects who visited the university hospital to be checked for glucose intolerance or known type 2 diabetes were consecutively recruited. Participants underwent an oral glucose tolerance test if they had no history of diabetes, and LV geometry and LV systolic and diastolic function were analyzed by Doppler echocardiography. RESULTS: The frequency of LV diastolic dysfunction in subjects with normal glucose tolerance, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), newly detected diabetes, and known diabetes were 13, 22, 50, 51, and 61%, respectively (χ(2) = 54.2, P < 0.0001). IGT was a predictor for LV diastolic dysfunction after adjusting for age, sex, systolic blood pressure, and heart rate (odds ratio 3.43 [95% CI 1.09-11.2]), but IFG was not (0.49 [0.06-3.08]). IGT was a predictor after adjusting for established CHF risk factors but was no longer significant after adjusting for BMI and homeostasis model assessment of insulin resistance. CONCLUSIONS: In this hospital-based registry of subjects without CHF, the prevalence of LV diastolic dysfunction was higher in subjects with IGT but not in those with IFG. Results suggest that IGT, as well as newly detected and known diabetes, could be linked to an increased risk of cardiovascular events, partly through LV diastolic dysfunction.

Diabetes Care.2011 Mar;34(3):686-90

Oxidative stress, endothelial dysfunction, and atherosclerosis.

This review focuses on the role of oxidative processes in atherosclerosis and the cardiovascular diseases (CVD) that can arise as a result. Atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. Overproduction of reactive oxygen species (ROS) under pathophysiologic conditions forms an integral part of the development of CVD, and in particular atherosclerosis. Endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not clear, oxidative stress seems to play an important role. In general, ROS are essential to the functions of cells, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects of excessive ROS production. In this review, we will provide a summary of the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as atherosclerosis; and currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases.

Curr Pharm Des. 2009;15(26):2988-3002

New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine.

Vitamin E (alpha-tocopherol or alphaT) has long been recognized as a classic free radical scavenging antioxidant whose deficiency impairs mammalian fertility. In actuality, alpha-tocopherol is one member of a class of phytochemicals that are distinguished by varying methylation of a chroman head group. Early studies conducted between 1922 and 1950 indicated that alpha-tocopherol was specific among the tocopherols in allowing fertility of laboratory animals. The unique vitamin action of alphaT, combined with its prevalence in the human body and the similar efficiency of tocopherols as chain-breaking antioxidants, led biologists to almost completely discount the "minor" tocopherols as topics for basic and clinical research. Recent discoveries have forced a serious reconsideration of this conventional wisdom. New and unexpected biological activities have been reported for the desmethyl tocopherols, such as gamma-tocopherol, and for specific tocopherol metabolites, most notably the carboxyethyl-hydroxychroman (CEHC) products. The activities of these other tocopherols do not map directly to their chemical antioxidant behavior but rather reflect anti-inflammatory, antineoplastic, and natriuretic functions possibly mediated through specific binding interactions. Moreover, a nascent body of epidemiological data suggests that gamma-tocopherol is a better negative risk factor for certain types of cancer and myocardial infarction than is a alpha-tocopherol. The potential public health implications are immense, given the extreme popularity of alphaT supplementation which can unintentionally deplete the body of gamma-tocopherol. These findings may or may not signal a major paradigm shift in free radical biology and medicine. The data argue for thorough experimental and epidemiological reappraisal of desmethyl tocopherols, especially within the contexts of cardiovascular disease and cancer biology.

Free Radic Biol Med.2004 Jan 1;36(1):1-15

A combination of aspirin and gamma-tocopherol is superior to that of aspirin and alpha-tocopherol in anti-inflammatory action and attenuation of aspirin-induced adverse effects.

Nonsteroidal anti-inflammatory drugs such as aspirin are used for pain relief and chemoprevention against cancer, but frequently cause gastric mucosal injury. We examined whether combinations of aspirin and alpha-tocopherol (alphaT) or aspirin and gamma-tocopherol (gammaT), with alphaT and gammaT being the two major forms of vitamin E, are better anti-inflammatory agents than aspirin alone, and whether these combinations alleviate aspirin-associated side effects. In the carrageenan-induced air-pouch inflammation model in the rat, aspirin (150 mg/kg) or a combination of aspirin and gammaT (33 mg/kg) inhibited proinflammatory prostaglandin E(2) (PGE(2)) by 70% (P<.02) at the inflammation site 6 h after inflammation was initiated. However, at 18 h, only the combination decreased exudate volume (15%; P<.05) and showed modest inhibition of PGE(2) (40%; P<.07) and lactate dehydrogenase activity (30%; P=.07) in the fluid collected at the inflammation site. gammaT, but not alphaT, spared aspirin-induced reduction in food intake, partially reversed aspirin-depressed gastric PGE(2) and attenuated stomach lesions. Surprisingly, the combination of aspirin and alphaT (33 mg/kg) did not show more benefits than aspirin alone, but worsened gastric injury and food intake reduction. Our study demonstrated that a combination of aspirin and gammaT, but not a combination of aspirin and alphaT, has some advantage over aspirin alone in terms of anti-inflammatory effects and attenuation of aspirin-induced adverse effects. This combination may be useful in complementing aspirin in the treatment of chronic inflammatory conditions and cancer.

J Nutr Biochem. 2009 Nov;20(11):894-900

Comparative uptake of alpha- and gamma-tocopherol by human endothelial cells.

The intake of gamma-tocopherol by North Americans is generally higher than that of alpha-tocopherol. However, the levels of alpha-tocopherol in human blood have consistently been shown to be higher than those of gamma-tocopherol suggesting differential cellular retention of the two tocopherol forms. We sought to resolve this question by studying tocopherol metabolism by human endothelial cells in culture. The time- and dose-dependent uptake of gamma-tocopherol by endothelial cells was similar to that of alpha-tocopherol. To determine the comparative uptake between alpha- and gamma-tocopherol, we adopted two approaches in which cells were enriched with either increasing concentrations of an equimolar mixture of alpha- and gamma-tocopherol; or cells were enriched with a fixed concentration of tocopherols in which the alpha to gamma ratio was varied. Our results indicated that there was a preferential uptake of gamma-tocopherol by the cells. When cells were enriched with either alpha- or gamma-tocopherol and the disappearance of individual tocopherols was monitored over time, gamma-tocopherol exhibited a faster rate of disappearance. The faster turnover of gamma-tocopherol can explain the discrepancy between high intake and low retention of gamma-tocopherol in man.

Lipids.1992 Jan;27(1):38-41

Supplementation of a γ-tocopherol-rich mixture of tocopherols in healthy men protects against vascular endothelial dysfunction induced by postprandial hyperglycemia.

Postprandial hyperglycemia induces oxidative stress responses, impairs vascular endothelial function (VEF) and increases the risk of cardiovascular disease. We hypothesized that the antioxidant and anti-inflammatory activities of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) would protect against vascular dysfunction that is otherwise caused by postprandial hyperglycemia by decreasing oxidative stress and proinflammatory responses, and improving nitric oxide (NO•) homeostasis. In a randomized, crossover study, healthy men (n=15; 21.8±0.8 years) completed a fasting oral glucose challenge (75 g) with or without prior supplementation of γ-TmT (5 days). Brachial artery flow-mediated dilation (FMD), plasma glucose, insulin, antioxidants, malondialdehyde (MDA), inflammatory proteins, arginine and asymmetric dimethylarginine (ADMA) were measured at regular intervals during a 3-h postprandial period. Supplementation of γ-TmT increased (P<.05) plasma γ-T by threefold and γ-carboxyethyl-hydroxychroman by more than ninefold without affecting α-T, glucose, arginine or ADMA. Baseline FMD, MDA, arginine and ADMA were unaffected by γ-TmT (P>.05). Postprandial FMD decreased 30%-44% (P<.05) following glucose ingestion, but was maintained with γ-TmT. Supplementation of γ-TmT also attenuated postprandial increases in MDA that occurred following glucose ingestion. Plasma arginine decreased (P<.05) in both trials to a similar extent regardless of γ-TmT supplementation. However, the ratio of ADMA/arginine increased time-dependently in both trials (P<.05), but to a lesser extent following γ-TmT supplementation (P<.05). Inflammatory proteins were unaffected by glucose ingestion or γ-TmT. Collectively, these findings support that short-term supplementation of γ-TmT maintains VEF during postprandial hyperglycemia possibly by attenuating lipid peroxidation and disruptions in NO• homeostasis, independent of inflammation.

J Nutr Biochem.2012 Jul 25

Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.

BACKGROUND: New diagnostic criteria for diabetes based on fasting blood glucose (FBG) level were approved by the American Diabetes Association. The impact of using FBG only has not been evaluated thoroughly. The fasting and the 2-hour glucose (2h-BG) criteria were compared with regard to the prediction of mortality. METHODS: Existing baseline data on glucose level at fasting and 2 hours after a 75-g oral glucose tolerance test from 10 prospective European cohort studies including 15,388 men and 7,126 women aged 30 to 89 years, with a median follow-up of 8.8 years, were analyzed. Hazards ratios for death from all causes, cardiovascular disease, coronary heart disease, and stroke were estimated. RESULTS: Multivariate Cox regression analyses showed that the inclusion of FBG did not add significant information on the prediction of 2h-BG alone (P>.10 for various causes), whereas the addition of 2h-BG to FBG criteria significantly improved the prediction (P<.001 for all causes and P<.005 for cardiovascular disease). In a model including FBG and 2h-BG simultaneously, hazards ratios (95% confidence intervals) in subjects with diabetes on 2h-BG were 1.73 (1.45-2.06) for all causes, 1.40 (1.02-1.92) for cardiovascular disease, 1.56 (1.03-2.36) for coronary heart disease, and 1.29 (0.66-2.54) for stroke mortality, compared with the normal 2h-BG group. Compared with the normal FBG group, the corresponding hazards ratios in subjects with diabetes on FBG were 1.21 (1.01-1.44), 1.20 (0.88-1.64), 1.09 (0.71-1.67), and 1.64 (0.88-3.07), respectively. The largest number of excess deaths was observed in subjects who had impaired glucose tolerance but normal FBG levels. CONCLUSION: The 2h-BG is a better predictor of deaths from all causes and cardiovascular disease than is FBG.

Arch Intern Med.2001 Feb 12;161(3):397-405

Hawthorn

Composition and health effects of phenolic compounds in hawthorn (Crataegus spp.) of different origins.

Epicatechin, aglycons and glycosides of B-type oligomeric procyanidins and flavonols, phenolic acids and C-glycosyl flavones are the major groups of phenolic compounds in hawthorn (Crataegus spp). The total content of phenolic compounds is higher in the leaves and flowers than in the fruits. Procyanidins dominate in the fruits, whereas flavonol glycosides and C-glycosyl flavones are most abundant in the leaves. Genotype and developmental/ripening stage have strong impacts. Procyanidin glycosides and C-glycosyl flavones may be chemotaxonomic markers differentiating species and varieties of hawthorn. Future research shall improve the separation, identification and quantification of procyanidins with degree of polymerisation (DP) ≥ 6, procyanidin glycosides, C-glycosyl flavones and some flavonol glycosides. In vitro and animal studies have shown cardioprotective, hypolipidaemic, hypotensive, antioxidant, radical-scavenging and anti-inflammatory potentials of hawthorn extracts, suggesting different phenolic compounds as the major bioactive components. However, the varying and insufficiently defined composition of the extracts investigated, as a result of different raw materials and extraction methods, makes comparison of the studies very difficult. Clinical evidence indicates that some hawthorn extracts may increase the exercise tolerance of patients with congestive heart failure. More clinical studies are needed to establish the effects of hawthorn, especially in healthy humans.

J Sci Food Agric.2012 Jun;92(8):1578-90

Terminalia arjuna in cardiovascular diseases: making the transition from traditional to modern medicine in India.

The stem bark of Terminalia arjuna (Roxb.) is used by the Ayurvedic physicians in India for the treatment of various cardiovascular diseases, collectively referred to as hritroga. It has been extensively studied in animal models to demonstrate cardioprotective properties, ranging from positive inotropic- , hypolipdemic-, coronary vasodilatory- and antioxidant effects to induction of stress protein in heart. Various bioactive compounds, like triterpinoids, tannins, flavonoids and minerals have been isolated from the stem bark. A number of clinical studies have also reported its beneficial effects in patients of chronic stable angina, endothelial dysfunction, heart failure and even ischemic mitral regurgitation. However, there are some identified lacunae, like standardisation of the 'drug', toxicity studies along with pharmacological interactions with other drugs and large multicentre randomized clinical trials, before its use by modern medicine is acceptable.

Curr Pharm Biotechnol.2010 Dec;11(8):855-60

The aqueous extract, not organic extracts, of Terminalia arjuna bark exerts cardiotonic effect on adult ventricular myocytes.

The bark of Terminalia arjuna (TA) has been used for centuries in ayurvedic medicine as cardiotonics for treatment of cardiac disorders. It became recently available as over-the-counter supplements marketed for maintaining a healthy heart. However, the cellular mechanism of its cardiotonic effect remains undefined. The present study was designed to investigate the physicochemical property and inotropic effect of the aqueous extract of TA bark (TA(AqE)) on adult rat ventricular myocytes in comparison with extracts prepared sequentially with organic solvents (organic extracts). The kinetics of myocyte contraction and caffeine-induced contraction were analyzed to assess the effect of TA(AqE) on sarcoplasmic reticular (SR) function. The inotropic effect of TA(AqE) was also compared with that of known cardiotonics, isoproterenol (ISO) and ouabain (Ouab). We found that TA(AqE) decoctions exerted positive inotropy, accelerated myocyte relaxation and increased caffeine-induced contraction concentration-dependently. In contrast, TA organic extracts caused interruption of excitability and arrhythmias without consistent inotropic action. In conclusion, TA(AqE)-induced cardiotonic action via enhancing SR function, a unique action minimizing the occurrence of arrhythmias, makes TA(AqE) a promising and relatively safe cardiotonic beneficial to the healthy heart and the treatment for chronic heart disease. The cardiotonic effect of TA(AqE) is consistent with the therapeutic property of TA bark used in ayurvedic medicine. The method of administration and/or selective omission of hydrophobic components from bark powder could be crucial to the efficacy and safety of TA bark in cardiac therapy and uses as over-the-counter supplements.

Phytomedicine.2011 Feb 15;18(4):259-65

Crataegus oxycantha extract attenuates apoptotic incidence in myocardial ischemia-reperfusion injury by regulating Akt and HIF-1 signaling pathways.

The objective of the present study was to evaluate the efficacy and mechanism of Crataegus oxycantha (COC) extract in preventing ischemia-reperfusion (IR) injury in an in vivo rat model of acute myocardial infarction induced by a 30-minute regional ischemia followed by 72 hours of reperfusion. The COC extract [100 mg/(kg body weight)] was administered 12 hours after the surgical procedure and then at 24-hour intervals for 3 days. Animals treated with COC extract showed a significant decrease in creatine kinase activity and infarct size. At the molecular level, COC administration resulted in a significant attenuation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) and upregulation of phospho-Akt and c-Raf levels in the heart. As a consequence, cleaved caspase-9 and cleaved caspase-7 levels were significantly downregulated, indicating negative regulation of apoptosis by COC extract. In part with the hypoxia-inducible factor (HIF) signaling pathway, COC extract administration significantly upregulated the prolyl hydroxylase-2 level. In contrast, other proapoptotic proteins such as nuclear factor-κB, cytochrome c, apoptosis-inducing factor, and cleaved poly(adenosine diphosphate-ribose) polymerase levels were significantly downregulated in the COC-treated group when compared with the untreated control group. The results suggested that COC extract attenuated apoptotic incidence in the experimental myocardial ischemia-reperfusion model by regulating Akt and HIF-1 signaling pathways.

J Cardiovasc Pharmacol.2010 Nov;56(5):526-31

Cardioprotective properties of Crataegus oxycantha extract against ischemia-reperfusion injury.

The aim of the study was to investigate the cardioprotective effect and mechanism of Crataegus oxycantha (COC) extract, a well-known natural antioxidant-based cardiotonic, against ischemia/reperfusion (I/R) injury. Electron paramagnetic resonance studies showed that COC extract was capable of scavenging superoxide, hydroxyl, and peroxyl radicals, in vitro. The cardioprotective efficacy of the extract was studied in a crystalloid perfused heart model of I/R injury. Hearts were subjected to 30min of global ischemia followed by 45min of reperfusion. During reperfusion, COC extract was infused at a dose rate of 1mg/ml/min for 10min. Hearts treated with COC extract showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase and lactate dehydrogenase activities. The expressions of xanthine oxidase and NADPH oxidase were significantly reduced in the treated group. A significant upregulation of the anti-apoptotic proteins Bcl-2 and Hsp70 with simultaneous downregulation of the pro-apoptotic proteins cytochrome c and cleaved caspase-3 was observed. The molecular signaling cascade including phospho-Akt (ser-473) and HIF-1alpha that lead to the activation or suppression of apoptotic pathway also showed a significant protective role in the treatment group. No significant change in phospho-p38 levels was observed. The results suggested that the COC extract may reduce the oxidative stress in the reperfused myocardium, and play a significant role in the inhibition of apoptotic pathways leading to cardioprotection.

Phytomedicine. 2010 Aug;17(10):744-52

Crataegus laevigata decreases neutrophil elastase and has hypolipidemic effect: a randomized, double-blind, placebo-controlled trial.

Crataegus laevigata is a medicinal plant most commonly used for the treatment of heart failure and psychosomatic disorders. Based on previous experimental findings, this double-blind placebo-controlled study was aimed at finding beneficial effects of C. laevigata on biomarkers of coronary heart disease (CHD). The study included 49 diabetic subjects with chronic CHD who were randomly assigned to the treatment for 6 months with either a micronized flower and leaf preparation of C. laevigata (400 mg three times a day) or a matching placebo. Blood cell count, lipid profile, C-reactive protein, neutrophil elastase (NE) and malondialdehyde were analyzed in plasma at baseline, at one month and six months. The main results were that NE decreased in the C. laevigata group compared to the placebo group. In the C. laevigata group, baseline figures (median and interquartile range) were 35.8 (4.5) and in the placebo group 31 (5.9). At the end of the study, values were 33.2 (4.7) ng/ml and 36.7 (2.2) ng/ml, respectively; p<0.0001. C. laevigata, added to statins, decreased LDL cholesterol (LDL-C) (mean±SD) from 105±28.5 mg/dl at baseline to 92.7±25.1 mg/dl at 6 months (p=0.03), and non-HDL cholesterol from 131±37.5 mg/dl to 119.6±33 mg/dl (p<0.001). Differences between groups did not reach statistical significance at 6 months. No significant changes were observed in the rest of parameters. In conclusion, C. laevigata decreased NE and showed a trend to lower LDL-C compared to placebo as add-on-treatment for diabetic subjects with chronic CHD.

Phytomedicine.2011 Jun 15;18(8-9):769-75

Antioxidant and hypocholesterolaemic effects of Terminalia arjuna tree-bark powder: a randomised placebo-controlled trial.

OBJECTIVE: To evaluate the antioxidant and hypocholesterolaemic effects of Terminalia arjuna tree bark (a popular cardiotonic substance in Indian pharmacopoeia) and to compare it with a known antioxidant, vitamin E, we performed a randomized controlled trial. METHODS: One hundred and five successive patients with coronary heart disease (CHD) presenting to our centre were recruited and using a Latin-square design divided into 3 groups of 35 each. The groups were matched for age, lifestyle and dietary variables, clinical diagnosis and drug treatment status. None of the patients was on lipid-lowering drugs. Supplemental vitamins were stopped for one month before study began and American Heart Association Step II dietary advice was given to all. At baseline, total cholesterol, triglycerides, HDL and LDL cholesterol and lipid peroxide estimated as thiobarbituric acid reactive substances (TBARS) were determined. Group I received placebo capsules; Group II vitamin E capsules 400 units/day; and Group III received finely pulverized T. arjuna tree bark-powder (500 mg) in capsules daily. Lipids and lipid peroxide levels were determined at 30 days follow-up. RESULTS: Response rate in various groups varied from 86% to 91%. No significant changes in total, HDL, LDL cholesterol and triglycerides levels were seen in Groups I and II (paired t-test p > 0.05). In Group III there was a significant decrease in total cholesterol (-9.7 +/- 12.7%), and LDL cholesterol (-15.8 +/- 25.6%) (paired t-test p < 0.01). Lipid peroxide levels decreased significantly in both the treatment groups (p < 0.01). This decrease was more in vitamin E group (-36.4 +/- 17.7%) as compared to the T. arjuna group (-29.3 +/- 18.9%). CONCLUSIONS: Terminalia arjuna tree bark powder has significant antioxidant action that is comparable to vitamin E. In addition, it also has a significant hypocholesterolaemic effect.

J Assoc Physicians India. 2001 Feb;49:231-5

Baseline severity but not gender modulates quantified Crataegus extract effects in early heart failure--a pooled analysis of clinical trials.

OBJECTIVE: The efficacy of quantified Crataegus extract in chronic heart failure (CHF) has been assessed in numerous clinical studies. The present pooled analysis evaluates the impact of baseline severity and gender on objective and patient-reported endpoints and associations between both types of outcomes in patients with early CHF. METHODS: Available data from 687 individual patients treated with quantified Crataegus extract or placebo in ten studies were pooled. Treatment effects on physiologic outcome parameters and on symptoms were analysed for their association with baseline severity and gender. Changes in symptom scores were investigated with respect to their relation to physiologic outcome parameters. Results were compared with observations in a 3-year cohort study. RESULTS: Physiologic outcome parameters maximal workload (MWL), left ventricular ejection fraction (LVEF) and pressure-heart rate product increase (PHRPI) at 50 W ergometric exercise improved more in active treatment than in placebo patients. Magnitude of improvement was independent from baseline for LVEF but increased for MWL and PHRPI with baseline severity. Improvement of typical symptoms like reduced exercise tolerance, exertional dyspnea, weakness, fatigue, and palpitations improved more with active treatment and in patients with more severe symptoms. A weak association between improvements in MWL, PRHP, and symptoms could be demonstrated. Gender differences in treatment effects could be explained by baseline differences. Results of the pooled analysis are in agreement with observations in the cohort study. CONCLUSIONS: Crataegus extract treatment effects on physiologic outcomes and typical symptoms were modulated by baseline severity. Taking baseline differences into account, benefits were comparable in male and female patients with impaired exercise-tolerance in early chronic heart-failure.

Phytomedicine. 2011 Nov 15;18(14):1214-9

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