Life Extension Magazine®

Issue: Sep 2014

Alpha-cyclodextrin

By Life Extension .

Quercetin alleviates hypercholesterolemic diet induced inflammation during progression and regression of atherosclerosis in rabbits.

OBJECTIVE: Recent advances have established a fundamental role for inflammation in mediating all stages of atherosclerosis, from initiation through progression. Quercetin may be a powerful bioactive constituent of the human diet, as a free radical scavenging agent and through interactions with various endogenous proteins. The present study focused on the effect of quercetin on inflammation induced by a hypercholesterolemic diet (HCD) in rabbits. METHODS: The animals were subjected to two different experiments, atherosclerotic progression and regression. In the atherosclerotic progression study, quercetin (25 mg/kg of body weight) was administered with the HCD for 90 d. In the atherosclerotic regression study, the animals were fed with the HCD for 90 d and then supplemented with quercetin (25 mg/kg of body weight) for another 90 d. The inflammatory enzyme activities were examined and a histopathologic examination of the aorta was performed. RESULTS: In the atherosclerotic progression study, quercetin co-administered with the HCD significantly decreased the activities of inflammatory enzymes such as cyclooxygenase, lipoxygenases (LOX) such as 5-LOX and 12-LOX in monocytes, nitric oxide synthase activity in the plasma, myeloperoxidase activity in the aorta, and the level of C-reactive protein in serum. In the regression study, quercetin administration significantly decreased the increased activities of inflammatory mediators such as cyclooxygenase, 5-LOX, 12-LOX, myeloperoxidase, and nitric oxide synthase and the serum level of C-reactive protein in HCD-fed rabbits compared with regression control rabbits. This effect was confirmed by histopathologic examination of the aorta.CONCLUSION: This study demonstrates that quercetin modulates the deleterious inflammatory effects induced by an HCD in vivo in rabbits, suggesting its beneficial effect in decreasing inflammation in atherosclerotic progression and regression.

Nutrition . 2013 Jan;29(1):219-29

Chronic intake of onion extract containing quercetin improved postprandial endothelial dysfunction in healthy men.

BACKGROUND: Epidemiologic studies have shown that dietary flavonoids reduce the risk of cardiovascular events. Onion is rich in quercetin, a strong antioxidant flavonoid. In some in vitro studies, quercetin improved endothelial function associated with atherosclerosis, a leading cause of cardiovascular events. OBJECTIVE: The aim of this study was to determine whether chronic onion extract intake would improve postprandial endothelial dysfunction induced by an oral maltose load in healthy men. METHODS: Healthy men (44±10 years, n=23) received 4.3 g of onion extract (containing 51 mg of quercetin) once a day for 30 days. Before and after the chronic onion extract intake, fasting and postprandial flow-mediated vasodilation (FMD) responses were measured. RESULTS: Maltose loading significantly decreased FMD both before and after chronic onion extract intake (p=0.000037 and p=0.0035, respectively). The chronic onion extract intake did not significantly affect fasting FMD (p=0.069) but improved the postprandial FMD significantly from 5.1%±2.2% to 6.7%±2.6% (p=0.00015). The chronic onion extract intake did not alter systemic and forearm hemodynamics. CONCLUSION: These findings suggest that chronic onion extract intake ameliorates postprandial endothelial dysfunction in healthy men and may be beneficial for improving cardiovascular health.

J Am Coll Nutr . 2013;32(3):160-4

Quercetin mitochondriotropic derivatives antagonize nitrate tolerance and endothelial dysfunction of isolated rat aorta rings.

Chronic use of glyceryl trinitrate is limited by serious side effects, inter alia tolerance and endothelial dysfunction of coronary and resistance arteries. The natural flavonoid quercetin has been shown to counteract the development of glyceryl trinitrate tolerance in vitro. Two mitochondriotropic, 4-O-triphenylphosphoniumbutyl derivatives of quercetin (QTA-3BTPI and Q-3BTPI) were compared to quercetin for protection against glyceryl trinitrate-induced tolerance and endothelial dysfunction of isolated rat aorta rings. Both QTA-3BTPI and Q-3BTPI significantly counteracted the reduced vascular responsiveness to both glyceryl trinitrate and acetylcholine caused by prolonged exposure of the vessel to glyceryl trinitrate itself, their potency being much greater than that of quercetin. QTA-3BTPI, however, turned out to cause endothelial dysfunction per se. Since Q-3BTPI antagonizedin vitro nitrate tolerance and endothelial dysfunction of vessels, this encourages assessing whether this effect is displayed also in vivo during long-term glyceryl trinitrate treatment.

Planta Med . 2013 Apr;79(6):465-7

Quercetin reduces oxidative stress and inhibits activation of cJun N-terminal kinase/activator protein1 signaling in an experimental mouse model of abdominal aortic aneurysm.

Oxidative stress is becoming increasingly linked to the pathogenesis of abdominal aortic aneurysms (AAAs). The antioxidant activity of flavonoids has attracted attention for their possible role in the prevention of cardiovascular diseases. The purpose of this study was to determine whether an antioxidant mechanism is involved in the aneurysm formation inhibitory effect afforded by quercetin. Male C57/BL6 mice received quercetin continuously from 2 weeks prior to and 6 weeks following the AAA induction with extraluminal CaCl2. Quercetin treatment decreased AAA incidence and inhibited the reactive oxygen species generation, nitrotyrosine formation and lipid peroxidation production in the aortic tissue during AAA development. In addition, quercetintreated mice exhibited significantly lower expression of the p47phox subunit of nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase, as well as coordinated downregulation of manganesesuperoxide dismutase activities and glutathione peroxidase (GPx)1 and GPx3 expression. Quercetin also blunted the expression of cJun N-terminal kinase (JNK) and phosphoJNK and, in addition, diminished activation of the activator protein (AP)1 transcription factor. Gelatin zymography showed that quercetin eliminated matrix metalloproteinase (MMP)2 and MMP9 activation during AAA formation. In conclusion, the inhibitory effects of quercetin on oxidative stress and MMP activation, through modulation of JNK/AP1 signaling, may partly account for its benefit in CaCl2 induced AAA.

Mol Med Rep . 2014 Feb;9(2):435-42

Protective effects of onion-derived quercetin on glutamate-mediated hippocampal neuronal cell death.

BACKGROUND: Neurodegener-ative diseases are characterized by progressive neuron degeneration in specific functional systems of the central or peripheral nervous system. This study investigated the protective effects of quercetin isolated from onion on neuronal cells and its protective mechanisms against glutamate-induced apoptosis in HT22 cells. MATERIALS AND METHODS: HT22 cells were cultured to study the neuroprotective mechanism of quercetin against glutamate-mediated oxidative stress. The intracellular reactive oxygen species (ROS) level and mitochondrial membrane potential (DYm) were measured. The protein expression of calpain, spectrin,Bcl-2, Bax, Bid, cytochrome c, and mitogen-activated protein kinases (MAPKs) was evaluated by Western blotting. RESULTS: Quercetin had a protective effect by reducing both intracellular ROS overproduction and glutamate-mediated Ca(2+) influx. These effects were due to the downregulation of several apoptosis-related biochemical markers. Calpain expression was reduced and spectrin cleavage was inhibited by quercetin in glutamate-exposed HT22 cells. Disruption of the mitochondrial membrane potential (DYm), activation of the pro-apoptotic proteins Bid and Bax, and cytochrome c release in response to glutamate-induced oxidative stress were reduced. Quercetin also suppressed phosphorylation of MAPKs. CONCLUSION: This is the first report on the detailed mechanisms of the protective effect of quercetin on HT22 cells. Onion extract and quercetin may be useful for preventing or treating neurodegenerative disorders.

Pharmacogn Mag . 2013 Oct;9(36):302-8

Quercetin up-regulates mitochondrial complex-I activity to protect against programmed cell death in rotenone model of Parkinson’s disease in rats.

We tested quercetin, a dietary bioflavonoid with potent free radical scavenging action and antioxidant activity, for its neuroprotective effects in rotenone-induced hemi-parkinsonian rats. Rats were infused unilaterally with rotenone into the substantia nigra, and quercetin (25-75mg/kg, i.p.) was administered at 12-h intervals for 4days, and analyzed on the 5th day. Amphetamine- or apomorphine-induced unilateral rotations were significantly reduced in quercetin-treated rats, when analyzed on 14th or 16th day post-surgery, respectively. Quercetin possessed potent hydroxyl radical scavenging action in a cells-free, Fenton-like reaction in test tubes, and in isolated mitochondria when measured by salicylate hydroxylation method. We observed dose-dependent attenuation of the rotenone-induced loss in striatal dopamine, and nigral oxidized and reduced glutathione, as well as the increases in endogenous antioxidant enzymes (catalase and superoxide dismutase) activities supporting the notion that quercetin-effect is mediated via its powerful hydroxyl radicals-scavenging and antioxidant actions. Quercetin’s dose-dependent ability to up-regulate mitochondrial complex-I activity, as evidenced by NADH-oxidation, and as seen in blue native-polyacrylamide gel electrophoresis (PAGE) staining in both the contra- and ipsi-lateral nigra suggests the containment of reactive oxygen production at the mitochondrial level. Rotenone-induced induction of NADH-diaphorase activity in the nigral neurons, and its attenuation by quercetin pointed to the possible involvement of nitric oxide too. Reversal of neuronal death induced by rotenone as observed by increased tyrosine hydroxylase-positive cells and decreased TdT-mediated dUTP nick end-labeling (TUNEL) staining in the substantia nigra confirmed the potential of quercetin to revamp dopaminergic cells following oxidative stress mediated programmed cell death and neuronal demise. The present study strongly implicates quercetin’s potential ability to repair mitochondrial electron transport defects and to up-regulate its function as the basis of neuroprotection observed in a mitochondrial neurotoxin-induced Parkinsonism.

Neuroscience . 2013 Apr 16;236:136-48

Effect of quercetin on traits of the metabolic syndrome, endothelial function and inflammation in men with different APOE isoforms.

BACKGROUND AND AIMS: The polyphenol quercetin may prevent cardiovascular diseases due to its vasorelaxant and anti-oxidative properties. We investigated the effects of quercetin on risk factors of atherosclerosis, biomarkers of inflammation and oxidative stress, depending on the apolipoprotein E (APOE) genotype. METHODS AND RESULTS: In a double-blind crossover study 49 healthy male subjects with APOE genotype 3/3 (n = 19), 3/4 (n = 22) and 4/4 (n = 8) consumed 150 mg/d quercetin or placebo for 8 weeks each, intermitted by a three-week washout phase. After each intervention, endothelial function, anthropometry, metabolic and inflammatory parameters were measured in the fasting and postprandial state following a standardized lipid-rich meal. Endothelial function was not changed. In all subjects combined, quercetin significantly decreased waist circumference (P = 0.004) and postprandial systolic blood pressure (P = 0.044). Postprandial triacylglycerol concentrations were significantly decreased and HDL-cholesterol concentrations increased after quercetin as compared to placebo consumption (P = 0.025). Quercetin also moderately increased levels of TNFa (P = 0.024). There was a significant gene-diet interaction for waist circumference and for body mass index (BMI). CONCLUSIONS: Quercetin supplementation improved some risk factors of cardiovascular disease, yet exerted slightly pro-inflammatory effects. Genotype-dependent effects were seen only on waist circumference and BMI.

Nutr Metab Cardiovasc Dis . 2013 May;23(5):403-9

The polyphenol quercetin protects the mev-1 mutant of Caenorhabditis elegans from glucose-induced reduction of survival under heat-stress depending on SIR-2.1, DAF-12, and proteasomal activity.

SCOPE: Hyperglycemia is a hallmark of diabetes mellitus but slighter increases of blood glucose levels are observed also during ageing. Using the Caenorhabditis elegans mev-1 mutant, we identified molecular mechanisms underlying the protection from glucose toxicity by the polyphenol quercetin. METHODS AND RESULTS: We fed C. elegans mev-1 mutants on a liquid medium supplemented with 10 mM glucose, which resulted in a reduced survival at 37°C. The polyphenol quercetin (1 µM) was able to prevent glucose-induced lifespan reduction completely. RNA interference revealed that the sirtuin SIR-2.1, the nuclear hormone receptor DAF-12, and its putative co-activator MDT-15 were critical for the quercetin effects. Moreover, RNA interference for key factors of proteostasis reduced survival, which was not further affected by glucose or quercetin, suggesting that those proteins are a target for both substances. Besides unfolded protein response, proper functionality of the proteasome was shown to be crucial for the survival enhancing effects of quercetin and the polyphenol was finally demonstrated to activate proteasomal degradation. CONCLUSION: Our studies demonstrate that lowest concentrations of quercetin prevent a glucose-induced reduction of survival. SIR-2.1, DAF-12, and MDT-15 were identified as targets that activate unfolded protein response and proteasomal degradation to limit the accumulation of functionally restricted proteins.

Mol Nutr Food Res . 2014 May;58(5):984-94

Quercetin reduces high-fat diet-induced fat accumulation in the liver by regulating lipid metabolism genes.

To understand the molecular mechanisms underlying the influence of quercetin on the physiological effects of hyperlipidemia, we investigated its role in the prevention of high-fat diet (HFD)-induced obesity and found that it regulated hepatic gene expression related to lipid metabolism. Quercetin supplementation in mice significantly reduced the HFD-induced gains in body weight, liver weight, and white adipose tissue weight compared with the mice fed only with HFD. It also significantly reduced HFD-induced increases in serum lipids, including cholesterol, triglyceride, and thiobarbituric acid-reactive substance (TBARS). Consistent with the reduced liver weight and white adipose tissue weight, hepatic lipid accumulation and the size of lipid droplets in the epididymal fat pads were also reduced by quercetin supplementation. To further investigate how quercetin may reduce obesity, we analyzed lipid metabolism-related genes in the liver. Quercetin supplementation altered expression profiles of several lipid metabolism-related genes, including Fnta, Pon1, Pparg, Aldh1b1, Apoa4, Abcg5, Gpam, Acaca, Cd36, Fdft1, and Fasn, relative to those in HFD control mice. The expression patterns of these genes observed by quantitative reverse transcriptase-polymerase chain reaction were confirmed by immunoblot assays. Collectively, our results indicate that quercetin prevents HFD-induced obesity in C57B1/6 mice, and its anti-obesity effects may be related to the regulation of lipogenesis at the level of transcription.

Phytother Res . 2013 Jan;27(1):139-43

Site-specific anticancer effects of dietary flavonoid quercetin.

Food-derived flavonoid quercetin, widely distributed in onions, apples, and tea, is able to inhibit growth of various cancer cells indicating that this compound can be considered as a good candidate for anticancer therapy. Although the exact mechanism of this action is not thoroughly understood, behaving as antioxidant and/or prooxidant as well as modulating different intracellular signaling cascades may all play a certain role. Such inhibitory activity of quercetin has been shown to depend first of all on cell lines and cancer types; however, no comprehensive site-specific analysis of this effect has been published. In this review article, cytotoxicity constants of quercetin measured in various human malignant cell lines of different origin were compiled from literature and a clear cancer selective action was demonstrated. The most sensitive malignant sites for quercetin revealed to be cancers of blood, brain, lung, uterine, and salivary gland as well as melanoma whereas cytotoxic activity was higher in more aggressive cells compared to the slowly growing cells showing that the most harmful cells for the organism are probably targeted. More research is needed to overcome the issues of poor water solubility and relatively low bioavailability of quercetin as the major obstacles limiting its clinical use.

Nutr Cancer . 2014;66(2):177-93

Dietary phylloquinone intake and risk of type 2 diabetes in elderly subjects athigh risk of cardiovascular disease.

BACKGROUND: Limited evidence from human and animal studies has suggested that vitamin K has a potentially beneficial role in glucose metabolism and insulin resistance. OBJECTIVE: We analyzed the cross-sectional and longitudinal associations between dietary phylloquinone intake and type 2 diabetes in elderly subjects at high cardiovascular risk. DESIGN: Cross-sectional associations were tested in 1,925 men and women in the Prevention with the Mediterranean Diet trial. A longitudinal analysis was conducted on 1069 individuals free of diabetes at baseline (median follow-up: 5.5 y). Biochemical and anthropometric variables were obtained yearly. Dietary intake was collected during each annual visit by using a food-frequency questionnaire, and phylloquinone intake was estimated by using the USDA database. The occurrence of type 2 diabetes during follow-up was assessed by using American Diabetes Association criteria. RESULTS: Dietary phylloquinone at baseline was significantly lower in subjects who developed type 2 diabetes during the study. After adjustment for potential confounders, risk of incident diabetes was 17% lower for each additional intake of 100 µg phylloquinone/d. Moreover, subjects who increased their dietary intake of vitamin K during the follow-up had a 51% reduced risk of incident diabetes compared with subjects who decreased or did not change the amount of phylloquinone intake. CONCLUSION: We conclude that dietary phylloquinone intake is associated with reduced risk of type 2 diabetes.

Am J Clin Nutr. 2012 Nov;96(5):1113-8

Dietary intake of vitamin K is inversely associated with mortality risk.

Vitamin K has been related to cardiovascular disease and cancer risk. However, data on total mortality are scarce. The aim of the present study was to assess the association between the dietary intake of different types of vitamin K and mortality in a Mediterranean population at high cardiovascular disease risk. A prospective cohort analysis was conducted in 7,216 participants from the PREDIMED (Prevención con Dieta Mediterránea) study (median follow-up of 4.8 y). Energy and nutrient intakes were evaluated using a validated 137-item food frequency questionnaire. Dietary vitamin K intake was calculated annually using the USDA food composition database and other published sources. Deaths were ascertained by an end-point adjudication committee unaware of the dietary habits of participants after they had reviewed medical records and linked up to the National Death Index. Cox proportional hazard models were fitted to assess the RR of mortality. Energy-adjusted baseline dietary phylloquinone intake was inversely associated with a significantly reduced risk of cancer and all-cause mortality after controlling for potential confounders (HR: 0.54; 95% CI: 0.30, 0.96; and HR: 0.64; 95% CI: 0.45, 0.90, respectively). In longitudinal assessments, individuals who increased their intake of phylloquinone or menaquinone during follow-up had a lower risk of cancer (HR: 0.64; 95% CI: 0.43, 0.95; and HR: 0.41; 95% CI: 0.26, 0.64, respectively) and all-cause mortality (HR: 0.57; 95% CI: 0.44, 0.73; and HR: 0.55; 95% CI: 0.42, 0.73, respectively) than individuals who decreased or did not change their intake. Also, individuals who increased their intake of dietary phylloquinone had a lower risk of cardiovascular mortality risk (HR: 0.52; 95% CI: 0.31, 0.86). However, no association between changes in menaquinone intake and cardiovascular mortality was observed (HR: 0.76; 95% CI: 0.44, 1.29). An increase in dietary intake of vitamin K is associated with a reduced risk of cardiovascular, cancer, or all-cause mortality in a Mediterranean population at high cardiovascular disease risk.

J Nutr. 2014 May;144(5):743-50

Dietary phylloquinone and menaquinones intakes and risk of type 2 diabetes.

OBJECTIVE: To investigate whether dietary phylloquinone and menaquinones intakes are related to risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: We used data from a prospective cohort study in 38,094 Dutch men and women, aged 20-70 years. Dietary phylloquinone and menaquinones intakes were assessed using a validated food frequency questionnaire. Diabetes case patients were ascertained mainly via self-report and verified against medical records. RESULTS: During 10.3 years of follow-up, 918 incident cases of diabetes were documented. In a multivariate model adjusting for diabetes risk factors and dietary factors, phylloquinone intake tended to be associated (P = 0.08) with a reduced risk of type 2 diabetes with a hazard ratio (HR) of 0.81 (95% CI 0.66-0.99) for the highest versus the lowest quartile. For menaquinones intake, a linear, inverse association (P = 0.038) with risk of type 2 diabetes was observed with an HR of 0.93 (0.87-1.00) for each 10-microg increment in the multivariate model. CONCLUSIONS: This study shows that both phylloquinone and menaquinones intakes may be associated with a reduced risk of type 2 diabetes.

Diabetes Care. 2010 Aug;33(8):1699-705

Dietary vitamin K and therapeutic warfarin alter the susceptibility to vascular calcification in experimental chronic kidney disease.

The leading cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease, with vascular calcification being a key modifier of disease progression. A local regulator of vascular calcification is vitamin K. This g-glutamyl carboxylase substrate is an essential cofactor in the activation of several extracellular matrix proteins that inhibit calcification. Warfarin, a common therapy in dialysis patients, inhibits the recycling of vitamin K and thereby decreases the inhibitory activity of these proteins. In this study, we sought to determine whether modifying vitamin K status, either by increasing dietary vitamin K intake or by antagonism with therapeutic doses of warfarin, could alter the development of vascular calcification in male Sprague-Dawley rats with adenine-induced CKD. Treatment of CKD rats with warfarin markedly increased pulse pressure and pulse wave velocity, as well as significantly increased calcium concentrations in the thoracic aorta (3-fold), abdominal aorta (8-fold), renal artery (4-fold), and carotid artery (20-fold). In contrast, treatment with high dietary vitamin K1 increased vitamin K tissue concentrations (10-300-fold) and blunted the development of vascular calcification. Thus, vitamin K has an important role in modifying mechanisms linked to the susceptibility of arteries to calcify in an experimental model of CKD.

Kidney Int. 2013 May;83(5):835-44

The realm of vitamin K dependent proteins: Shifting from coagulation toward calcification.

In the past few decades vitamin K has emerged from a single-function “hemostasis vitamin” to a “multi-function vitamin.” The use of vitamin K antagonists (VKA) inevitably showed that the inhibition was not restricted to vitamin K dependent coagulation factors but also synthesis of functional extrahepatic vitamin K dependent proteins (VKDPs), thereby eliciting undesired side effects. Vascular calcification is one of the recently revealed detrimental effects of VKA. The discovery that VKDPs are involved in vascular calcification has propelled our mechanistic understanding of this process and has opened novel avenues for diagnosis and treatment. This review addresses mechanisms of VKDPs and their significance for physiological and pathological calcification.

Mol Nutr Food Res. 2014 Feb 17

Vitamin K status and vascular calcification: evidence from observational and clinical studies.

Vascular calcification occurs when calcium accumulates in the intima (associated with atherosclerosis) and/or media layers of the vessel wall. Coronary artery calcification (CAC) reflects the calcium burden within the intima and media of the coronary arteries. In population-based studies, CAC independently predicts cardiovascular disease (CVD) and mortality. A preventive role for vitamin K in vascular calcification has been proposed based on its role in activating matrix Gla protein (MGP), a calcification inhibitor that is expressed in vascular tissue. Although animal and in vitro data support this role of vitamin K, overall data from human studies are inconsistent. The majority of population-based studies have relied on vitamin K intake to measure status. Phylloquinone is the primary dietary form of vitamin K and available supplementation trials, albeit limited, suggest phylloquinone supplementation is relevant to CAC. Yet observational studies have found higher dietary menaquinone, but not phylloquinone, to be associated with less calcification. Vascular calcification is highly prevalent in certain patient populations, especially in those with chronic kidney disease (CKD), and it is plausible vitamin K may contribute to reducing vascular calcification in patients at higher risk. Subclinical vitamin K deficiency has been reported in CKD patients, but studies linking vitamin K status to calcification outcomes in CKD are needed to clarify whether or not improving vitamin K status is associated with improved vascular health in CKD. This review summarizes the available evidence of vitamin K and vascular calcification in population-based studies and clinic-based studies, with a specific focus on CKD patients.

Adv Nutr. 2012 Mar 1;3(2):158-65

The levels of plasma growth arrest-specific protein 6 is associated with insulin sensitivity and inflammation in women.

AIMS: Vitamin K-dependent growth arrest-specific protein 6 (Gas6) and its receptors of the TAM (TYRO-3/Axl/Mer) family are ubiquitously expressed in immune, cardiovascular, and reproductive systems. They play pivotal roles of regulating tissue homeostasis via anti-inflammatory effects. Recent studies show that the Gas6/TAM system is involved in glucose tolerance-related metabolic disorders. Our aim was to investigate the link between Gas6 protein, insulin sensitivity and inflammatory cytokines in men and women. METHODS: A total of 278 adults (126 men and 152 women) were recruited in this study. Plasma Gas6 concentration and various biochemical, proinflammatory and endothelial markers were measured. Insulin sensitivity was estimated by homeostasis model assessment. RESULTS: Waist, fasting and 2h post-load glucose, and glycated hemoglobin (HbA1C) were significantly lower in women than in men. Age, high-density lipoprotein cholesterol, and highly-sensitive C-reactive protein levels were significantly higher in women than in men. Plasma Gas6 levels were negatively correlated with waist (r = -0.187, P = 0.022), HOMA-IR (r = -0.171, P=0.035), interleukin 6 (r = -0.362, P < 0.001), and E-selectin (r = -0.216, P = 0.008), while they were positively correlated with insulin sensitivity (QUICKI) (r = 0.168, P = 0.039) in women, but not in men. Stepwise multiple regression analysis showed that TNF-a was independently correlated with plasma Gas6 levels in both the sexes (P < 0.001). CONCLUSION: Plasma Gas6 is associated with obesity, insulin sensitivity, inflammation, and endothelial dysfunction in women and may be a general marker of inflammatory conditions in women.

Diabetes Res Clin Pract. 2014 Feb;103(2):304-9

Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women.

INTRODUCTION: Despite contradictory data on vitamin K supplementation and bone health, the European Food Safety Authorities (EFSA) accepted the health claim on vitamin K’s role in maintenance of normal bone. In line with EFSA’s opinion, we showed that 3-year high-dose vitamin K1 (phylloquinone) and K2 (short-chain menaquinone-4) supplementation improved bone health after menopause. Because of the longer half-life and greater potency of the long-chain MK-7, we have extended these investigations by measuring the effect of low-dose MK-7 supplementation on bone health. METHODS: Healthy postmenopausal women (n = 244) received for 3 years placebo or MK-7 (180 µg MK-7/day) capsules. Bone mineral density of lumbar spine, total hip, and femoral neck was measured by DXA; bone strength indices of the femoral neck were calculated. Vertebral fracture assessment was performed by DXA and used as measure for vertebral fractures. Circulating uncarboxylated osteocalcin (ucOC) and carboxylated OC (cOC) were measured; the ucOC/cOC ratio served as marker of vitamin K status. Measurements occurred at baseline and after 1, 2, and 3 years of treatment. RESULTS: MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae. CONCLUSIONS: MK-7 supplements may help postmenopausal women to prevent bone loss. Whether these results can be extrapolated to other populations, e.g., children and men, needs further investigation.

Osteoporos Int . 2013 Sep;24(9):2499-507

Bone quality and vitamin K2 in type 2 diabetes: review of preclinical and clinical studies.

Type 2 diabetic patients are at high risk of bone fractures even if their bone mineral density is normal or high. This is likely explained by poor bone quality and extraskeletal factors. The present review was conducted to provide an overview of the currently available preclinical and clinical evidence on the effect of vitamin K(2) on bone quality in persons with type 2 diabetes. Vitamin K(2) stimulates g-carboxylation of osteocalcin and can increase bone formation through steroid and xenobiotic receptors. Clinical studies of type 2 diabetic patients have shown detrimental collagen cross-links in bone; low serum insulin-like growth factor-I and osteocalcin concentration are associated with an increased risk of fractures. A therapeutic strategy for preventing fractures in type 2 diabetic patients remains to be established. One recent preclinical study showed that vitamin K(2) administration in a type 2 diabetic rat model had the following skeletal benefits: increased serum osteocalcin, improved collagen cross-link profiles, and increased bone strength. These new findings suggesting a possible beneficial effect of vitamin K(2) supplementation on bone quality in type 2 diabetes warrant further investigation.

Nutr Rev . 2011 Mar;69(3):162-7

Vitamin k2, a naturally occurring menaquinone, exerts therapeutic effects on both hormone-dependent and hormone-independent prostate cancer cells.

In recent years, several studies have shown that vitamin k2 (VK2) has anticancer activity in a variety of cancer cells. The antitumor effects of VK2 in prostate cancer are currently not known. In the present study, we sought to characterize the anticancer potential of VK2 in both androgen-dependent and -independent prostate cancer cells. Our investigations show that VK2 is able to suppress viability of androgen-dependent and androgen-independent prostate cancer cells via caspase-3 and -8 dependent apoptosis. We also show that VK2 treatment reduces androgen receptor expression and PSA secretion in androgen-dependent prostate cancer cells. Our results also implicate VK2 as a potential anti-inflammatory agent, as several inflammatory genes are downregulated in prostate cancer cells following treatment with VK2. Additionally, AKT and NF-kB levels in prostate cancer cells are reduced significantly when treated with VK2. These findings correlated with the results of the Boyden chamber and angiogenesis assay, as VK2 treatment reduced cell migration and angiogenesis potential of prostate cancer cells. Finally, in a nude mice model, VK2 administration resulted in significant inhibition of both androgen-dependent and androgen-independent tumor growth. Overall, our results suggest that VK2 may be a potential therapeutic agent in the treatment of prostate cancer.

Evid Based Complement Alternat Med . 2013;2013:287358

Efficacy of tart cherry Juice to reduce inflammation among patients with osteoarthritis

Background: Osteoarthritis (OA) is a major cause of pain and disability. OA patients may find relief from the inflammatory component of OA with NSAID use. Tart cherries, high in antioxidant and anti-inflammatory properties, may reduce pain and inflammation without the adverse side effects of NSAIDs. This study aimed to assess the effects of tart cherry juice as compared to a placebo cherry drink on serum biomarkers among inflammatory OA subjects.Methods: The design was a randomized, double-blind, placebo-controlled trial. Twenty inflammatory OA subjects (all female; 40-70 yrs) consumed 10.5 oz bottles of tart cherry juice or placebo cherry drink twice daily for 21 consecutive days. Participants assessed level of pain at baseline and after the intervention. Blood samples were collected at baseline and final visit to assess the biomarkers of inflammation: C-Reactive Protein (CRP), Interleukin-6 (IL-6), Interleukin-10 (IL-10), and Tumor Necrosis Factor-alpha (TMF-a). Data are reported as mean +/- SD for pre and post serum biomarkers. Results: Subjects on the tart cherry juice showed a statistically significant reduction in the serum biomarker CRP (p<0.05). Conclusions: Tart cherry juice may reduce inflammation as measured by certain serum inflammatory biomarkers among women with OA.

Journal of Food Studies. 2012;1(1)

Cherries and health: a review.

Cherries, and in particular sweet cherries, are a nutritionally dense food rich in anthocyanins, quercetin, hydroxycinnamates, potassium, fiber, vitamin C, carotenoids, and melatonin. UV concentration, degree of ripeness, postharvest storage conditions, and processing, each can significantly alter the amounts of nutrients and bioactive components. These constituent nutrients and bioactive food components support the potential preventive health benefits of cherry intake in relation to cancer, cardiovascular disease, diabetes, inflammatory diseases, and Alzheimer’s disease. Mechanistically, cherries exhibit relatively high antioxidant activity, low glycemic response, COX 1 and 2 enzyme inhibition, and other anti-carcinogenic effects in vitro and in animal experiments. Well-designed cherry feeding studies are needed to further substantiate any health benefits in humans.

Crit Rev Food Sci Nutr . 2011 Jan;51(1):1-12

Anthocyanin content, lipid peroxidation and cyclooxygenase enzyme inhibitory activities of sweet and sour cherries.

Cherries contain bioactive anthocyanins that are reported to possess antioxidant, anti-inflammatory, anticancer, antidiabetic, and antiobese properties. The present study revealed that red sweet cherries contained cyanidin-3-O-rutinoside as major anthocyanin (>95%). The sweet cherry cultivar “Kordia” (aka “Attika”) showed the highest cyanidin-3-O-rutinoside content, 185 mg/100 g fresh weight. The red sweet cherries “Regina” and “Skeena” were similar to “Kordia”, yielding cyanidin-3-O-rutinoside at 159 and 134 mg/100 g fresh weight, respectively. The yields of cyanidin-3-O-glucosylrutinoside and cyanidin-3-O-rutinoside were 57 and 19 mg/100 g fresh weight in “Balaton” and 21 and 6.2 mg/100 g fresh weight in “Montmorency”, respectively, in addition to minor quantities of cyanidin-3-O-glucoside. The water extracts of “Kordia”, “Regina”, “Glacier” and”Skeena” sweet cherries gave 89, 80, 80 and 70% of lipid peroxidation (LPO) inhibition, whereas extracts of “Balaton” and “Montmorency” were in the range of 38 to 58% at 250 microg/mL. Methanol and ethyl acetate extracts of the yellow sweet cherry “Rainier” containing beta-carotene, ursolic, coumaric, ferulic and cafeic acids inhibited LPO by 78 and 79%, respectively, at 250 microg/mL. In the cyclooxygenase (COX) enzyme inhibitory assay, the red sweet cherry water extracts inhibited the enzymes by 80, to 95% at 250 microg/mL. However, the methanol and ethyl acetate extracts of “Rainier” and “Gold” were the most active against COX-1 and -2 enzymes. Water extracts of “Balaton” and “Montmorency” inhibited COX-1 and -2 enzymes by 84, and 91 and 77, and 87%, respectively, at 250 microg/mL.

J Agric Food Chem . 2009 Feb 25;57(4):1239-46

Tart cherry-enriched diets reduce atherosclerosis and mortality in mice

Epidemiologic data suggest that anthocyanin intake is inversely related to cardiac mortality. In animals, intake of anthocyanin-rich tart cherries reduces cardiovascular risk factors, but the specific effect upon atherosclerosis is unknown. Male ApoE-null mice were provided diet containing 21% total fat. A cohort of ApoE-null mice were provided 1% of the diet as tart cherry powder from pitted, individually quick frozen tart cherries. Diets were matched for calorie and carbohydrate content. Mice were sacrificed after five months of feeding. Cherry intake reduced serum oxidative stress marker malonyldialdehyde (–17%), inflammation marker C-reactive protein(–36%), and total cholesterol(–26%). Cherry intake also reduced early mortality (–65%) and reduced lipid deposition in the aortic arch(–29%) and abdominal aorta(–8%). Several inflammation-related mRNAs and proteins were altered in aortas of cherry-fed mice including tumor necrosis factor-a and monocyte chemotactic protein-1. However, mRNA related to lipid uptake and storage were unchanged. The data suggest that cherry intake may have reduced atherosclerosis by reduced serum cholesterol and/or reduced local inflammation in the aortic wall, but not by altered cholesterol uptake, itself. In conclusion, anthocyanin-rich tart cherry intake reduced atherosclerosis, biomarkers of cardiovascular risk, and atherosclerosis-related mortality.

The FASEB Journal . 2011;25:980

Regular tart cherry intake alters abdominal adiposity, adipose gene transcription, and inflammation in obesity-prone rats fed a high fat diet.

Obesity, systemic inflammation, and hyperlipidemia are among the components of metabolic syndrome, a spectrum of phenotypes that can precede the development of type 2 diabetes and cardiovascular disease. Animal studies show that intake of anthocyanin-rich extracts can affect these phenotypes. Anthocyanins can alter the activity of tissue peroxisome proliferator-activated receptors (PPARs), which affect energy substrate metabolism and inflammation. However, it is unknown if physiologically relevant, anthocyanin-containing whole foods confer similar effects to concentrated, anthocyanin extracts. The effect of anthocyanin-rich tart cherries was tested in the Zucker fatty rat model of obesity and metabolic syndrome. For 90 days, rats were pair-fed a higher fat diet supplemented with either 1% (wt/wt) freeze-dried, whole tart cherry powder or with a calorie- and macronutrient-matched control diet. Tart cherry intake was associated with reduced hyperlipidemia, percentage fat mass, abdominal fat (retroperitoneal) weight, retroperitoneal interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) expression, and plasma IL-6 and TNF-alpha. Tart cherry diet also increased retroperitoneal fat PPAR-alpha and PPAR-gamma mRNA (P = .12), decreased IL-6 and TNF-alpha mRNA, and decreased nuclear factor kappa B activity. In conclusion, in at-risk obese rats fed a high fat diet, physiologically relevant tart cherry consumption reduced several phenotypes of metabolic syndrome and reduced both systemic and local inflammation. Tart cherries may reduce the degree or trajectory of metabolic syndrome, thereby reducing risk for the development of type 2 diabetes and heart disease.

J Med Food . 2009 Oct;12(5):935-42

Cherry consumption and decreased risk of recurrent gout attacks.

OBJECTIVE: To study the relationship between cherry intake and the risk of recurrent gout attacks among individuals with gout. METHODS: We conducted a case-crossover study to examine the associations of a set of putative risk factors with recurrent gout attacks. Individuals with gout were prospectively recruited and followed up online for 1 year. Participants were asked to provide the following information regarding gout attacks: the onset date of the gout attack, symptoms and signs, medications (including antigout medications), and exposure to potential risk factors (including daily intake of cherries and cherry extract) during the 2-day period prior to the gout attack. We assessed the same exposure information over 2-day control periods. We estimated the risk of recurrent gout attacks related to cherry intake using conditional logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Our study included 633 individuals with gout. Cherry intake over a 2-day period was associated with a 35% lower risk of gout attacks compared with no intake (multivariate OR 0.65 [95% CI 0.50-0.85]). Cherry extract intake showed a similar inverse association (multivariate OR 0.55 [95% CI 0.30-0.98]). The effect of cherry intake persisted across subgroups stratified by sex, obesity status, purine intake, alcohol use, diuretic use, and use of antigout medications. When cherry intake was combined with allopurinol use, the risk of gout attacks was 75% lower than during periods without either exposure (OR 0.25 [95% CI 0.15-0.42]). CONCLUSION: These findings suggest that cherry intake is associated with a lower risk of gout attacks.

Arthritis Rheum . 2012 Dec;64(12):4004-11

Efficacy of tart cherry juice in reducing muscle pain during running: a randomized controlled trial.

BACKGROUND: Long distance running causes acute muscle damage resulting in inflammation and decreased force production. Endurance athletes use NSAIDs during competition to prevent or reduce pain, which carries the risk of adverse effects. Tart cherries, rich in antioxidant and anti-inflammatory properties, may have a protective effect to reduce muscle damage and pain during strenuous exercise. This study aimed to assess the effects of tart cherry juice as compared to a placebo cherry drink on pain among runners in a long distance relay race. METHODS: The design was a randomized, double-blind, placebocontrolled trial. Fifty-four healthy runners (36 male, 18 female; 35.8 +/- 9.6 yrs) ran an average of 26.3 +/- 2.5 km over a 24 hour period. Participants ingested 355 mL bottles of tart cherry juice or placebo cherry drink twice daily for 7 days prior to the event and on the day of the race. Participants assessed level of pain on a standard 100 mm Visual Analog Scale (VAS) at baseline, before the race, and after the race. RESULTS: While both groups reported increased pain after the race, the cherry juice group reported a significantly smaller increase in pain (12 +/- 18 mm) compared to the placebo group (37 +/- 20 mm) (p < .001). Participants in the cherry juice group were more willing to use the drink in the future (p < 0.001) and reported higher satisfaction with the pain reduction they attributed to the drink (p < 0.001). CONCLUSIONS: Ingesting tart cherry juice for 7 days prior to and during a strenuous running event can minimize post-run muscle pain.

J Int Soc Sports Nutr . 2010 May 7;7:17

Montmorency cherry juice reduces muscle damage caused by intensive strength exercise.

PURPOSE: Montmorency cherries contain high levels of polyphenolic compounds including flavonoids and anthocyanins possessing antioxidant and anti-inflammatory effects. We investigated whether the effects of intensive unilateral leg exercise on oxidative damage and muscle function were attenuated by consumption of a Montmorency cherry juice concentrate using a crossover experimental design. METHODS: Ten well-trained male overnight-fasted athletes completed two trials of 10 sets of 10 single-leg knee extensions at 80% one-repetition maximum. Trials were separated by 2 wk, and alternate legs were used in each trial. Participants consumed each supplement (CherryActive® (CA) or isoenergetic fruit concentrate (FC)) for 7 d before and 48 h after exercise. Knee extension maximum voluntary contractions (MVC) were performed before, immediately after, and 24 and 48 h after the damaging exercise. Venous blood samples were collected at each time point, and serum was analyzed for creatine kinase (CK) activity, nitrotyrosine, high-sensitivity C-reactive protein, total antioxidant capacity, and protein carbonyls (PC). Two-way repeated-measures ANOVA were used for statistical analysis of the data. RESULTS: MVC force recovery was significantly faster (24 h: CA 90.9% ± 4.2% of initial MVC vs FC 84.9% ± 3.4% of initial MVC; 48 h: CA 92.9% ± 3.3% of initial MVC vs FC 88.5% ± 2.9% of initial MVC (mean ± SEM); P < 0.05) after CA than FC consumption. Only serum CK and PC increased significantly from baseline, peaking 24 h after exercise (P < 0.001). The exercise-induced increase in CK activity was not different between trials. However, both the percentage (24 h after: CA 23.8% ± 2.9% vs FC 82.7% ± 11.7%; P = 0.013) and absolute (24 h after: CA 0.31 ± 0.03 nmol·mg(-1) protein vs FC 0.60 ± 0.08 nmol·mg(-1) protein; P = 0.079) increase in PC was lower in CA than FC trials. CONCLUSIONS: Montmorency cherry juice consumption improved the recovery of isometric muscle strength after intensive exercise perhaps owing to the attenuation of the oxidative damage induced by the damaging exercise.

Med Sci Sports Exerc . 2011 Aug;43(8):1544-51

Improved antioxidant and anti-inflammatory potential in mice consuming sour cherry juice (Prunus Cerasus cv. Maraska).

The present investigation tested the in vivo antioxidant efficacy (superoxide dismutase, SOD;
catalase, CAT; glutathione peroxidase; Gpx), lipid peroxidation (LPO) and anti-inflammatory properties (cyclooxygenase-2; COX-2) of sour cherry juices obtained from an autochthonous cultivar (Prunus cerasus cv. Maraska) that is grown in coastal parts of Croatia. Antioxidant potential was tested in mouse tissue (blood, liver, and brain), LPO (liver, brain) and anti-inflammatory properties in glycogen elicited macrophages. Additionally, the concentration of cyanidin-3-glucoside, cyanidin-3-rutinoside, pelargonidin-3-glucoside, pelargonidin-3-rutinoside and total anthocyanins present in Prunus cerasus cv. Maraska cherry juice was determined. Mice were randomly divided into a control group (fed with commercial food pellets) and 2 experimental groups (fed with commercial food pellets with 10% or 50% of cherry juice added). Among the anthocyanins, the cyanidin-3-glucoside was present in the highest concentration. These results show antioxidant action of cherry juice through increased SOD (liver, blood) and Gpx (liver) activity and decreased LPO concentration. The study highlights cherry juice as a potent COX-2 inhibitor and antioxidant in the liver and blood of mice, but not in the brain. Thus, according to our study, Prunus cerasus cv. Maraska cherry juice might potentially be used as an antioxidant and anti-inflammatory product with beneficial health-promoting properties.

Plant Foods Hum Nutr . 2009 Dec;64(4):231-7

Anti-diabetic effect of cherries in alloxan induced diabetic rats.

Diabetes mellitus (DM) is a metabolic disorder in the endocrine system resulting from a defect in insulin secretion, insulin action or both of them. Adverse side effects of chemical drugs for treatment of diabetes persuaded the using of medical plants. Cherry as a traditionally used plant for treatment of diabetes, is packed with powerful plant pigments called anthocyanins. They give cherries their dark red color and are one of the richest antioxidant sources which lower the blood sugar and bear other beneficial health effects. The purpose of this study is to evaluate the effect of ethanolic extract of cherry fruit on alloxan induced diabetic rats. In this study 36 Male Wistar rats, body weight of 150-200gr were divided into 6 groups. Diabetes was induced by intra peritoneal injection of 120 mg/kg Alloxan. The duration of the cherries treatment was 30 days in which single dose of extracts (200mg/kg) were oral administered to diabetic rats. Blood glucose levels were estimated with glucometer before treatment, 2h and 1-4 weeks after administration of extracts. Treatment with extracts of the cherries resulted in a significant reduction in blood glucose and urinary microalbumin and an increase in the creatinine secretion level in urea. Extract of this plant is useful in controlling the blood glucose level. Cherries appear to aid in diabetes control and diminution of the complications of the disease. Some relevant patents are also outlined in this article.

Recent Pat Endocr Metab Immune Drug Discov . 2012 Jan;6(1):67-72

Orlistat-induced oxalate nephropathy may be dose-independent and present as a late manifestation.

We present the case of a 61-year-old Caucasian male veteran who had been on orlistat (120mg dosing) for four years, and had changed to the over-the-counter (OTC) form, Alli (orlistat 60mg), about three months before presentation. He had been experiencing nausea and vomiting for three weeks prior to evaluation. Laboratory studies revealed a serum creatinine of 6.2 mg/dL—his previous renal function having been normal. An ultrasound-guided renal biopsy was performed, which revealed deposition of calcium oxalate crystals in the renal tubules. Orlistat is a popular weight-loss medication. Orlistat-induced oxalate crystal nephropathy has recently been reported in the literature, resulting from the original, patented version. We report a case with the first such complication from the OTC version, Alli which is a reduced-dose formulation. Our case report highlights that this complication can occur after several years of use of the medication and is not necessarily dose dependent.

J La State Med Soc . 2013 Sep-Oct;165(5):283-5

Dietary alpha-cyclodextrin lowers low-density lipoprotein cholesterol and alters plasma fatty acid profile in low-density lipoprotein receptor knockout mice on a high-fat diet.

High dietary intake of saturated fat and cholesterol, and elevated low-density lipoprotein cholesterol levels are some of the modifiable risk factors for cardiovascular disease. Alpha-cyclodextrin (a-CD) when given orally has been shown in rats to increase fecal saturated fat excretion and to reduce blood total cholesterol levels in obese hypertriglyceridemic subjects with type 2 diabetes mellitus. In this study, the effects of dietary a-CD on lipid metabolism in low-density lipoprotein receptor knockout mice were investigated. Low-density lipoprotein receptor knockout mice were fed a “Western diet” (21% milk fat) with or without 2.1% of a-CD (10% of dietary fat content) for 14 weeks. At sacrifice, there was no difference in body weight; but significant decreases were observed in plasma cholesterol (15.3%), free cholesterol (20%), cholesterol esters (14%), and phospholipid (17.5%) levels in mice treated with alpha-CD compared with control mice. The decrease in total cholesterol was primarily in the proatherogenic apolipoprotein B-containing lipoprotein fractions, with no significant change in the high-density lipoprotein fraction. Furthermore, alpha-CD improved the blood fatty acid profile, reducing the saturated fatty acids (4.5%) and trans-isomers (11%) while increasing (2.5%) unsaturated fatty acids. In summary, the addition of alpha-CD improved the lipid profile by lowering proatherogenic lipoproteins and trans-fatty acids and by decreasing the ratio of saturated and trans-fatty acids to polyunsaturated fatty acids (-5.8%), thus suggesting that it may be useful as a dietary supplement for reducing cardiovascular disease.

Metabolism . 2008 Aug;57(8):1046-51

The effect of a-cyclodextrin on postprandial lipid and glycemic responses to a fat-containing meal.

OBJECTIVE: a-Cyclodextrin (a-CD), a soluble dietary fiber derived from corn, marketed under the trade name FBCx®, has the potential to help individuals manage their weight and improve their lipid profiles. Initial studies in healthy overweight and/or obese diabetic individuals found that, in those consuming a normal to high fat diet over a 4 or 12 week period, a-CD use was associated with weight loss or maintenance and a reduction in triglyceride (TG) and cholesterol levels in hyperlipidemic individuals. Furthermore, a-CD use was associated with the positive effects of increasing insulin and leptin sensitivities. To date, the immediate post-prandial glucose and lipid responses to a fat-containing meal have not been reported. MATERIALS/METHOD: This double blinded placebo controlled cross-over trial examined the effect of 2 g of a-CD taken immediately following consumption of a commercially prepared high-fat breakfast meal on the acute postprandial responses in healthy adults. RESULTS: The coincidental consumption of a-CD with a fat-containing meal was associated with a significant reduction in postprandial TG responses over time when compared to placebo. When incremental area under the curve was calculated, the area under the curve associated with a-CD consumption was significantly smaller than the placebo area (0.30±1.07 mmol/L/3 h vs. 0.98±0.88 mmol/L/3 h, p<0.05). There were no significant changes in glucose or cholesterol levels. CONCLUSION: a-Cyclodextrin was shown to significantly lower acute postprandial blood triglyceride levels.

Metabolism . 2013 Oct;62(10):1443-7

The beneficial effects of a-cyclodextrin on blood lipids and weight loss in healthy humans.

a-Cyclodextrin (a-CD) is a soluble fiber derived from corn. It has previously been reported that early intervention with Mirafit fbcx, a trademarked name for a-CD, has beneficial effects on weight management in obese individuals with type 2 diabetes, and that it preferentially reduces blood levels of saturated and trans fats in the LDL receptor knockout mice. The current investigation involves overweight but not obese nondiabetic individuals and was intended to confirm the effects of a-CD on both weight management and improving blood lipid levels. Forty-one healthy adults (age: 41.4 ± 13.6 years) participated in this 2-month, double-blinded, crossover study. In 28 compliant participants (8 males and 20 females), when the active phase was compared to the control phase, there were significant decreases in body weight (-0.4 ± 0.2 kg, P < 0.05), serum total cholesterol (mean ± s.e.m., -0.295 ± 0.10 mmol/l, 5.3%, P < 0.02) and low-density lipoprotein (LDL) cholesterol (-0.23 ± 0.11 mmol/l, -6.7%, P < 0.05). Apolipoprotein B (Apo B) (-0.0404 ± 0.02 g/l, -5.6%, P = 0.06) and insulin levels also decreased by 9.5% (-0.16 ± 0.08 pmol/l, P = 0.06) while blood glucose and leptin levels did not change. These results suggest that a-CD exerts its beneficial health effects on body weight and blood lipid profile in healthy nonobese individuals, as previously reported in obese individuals with type 2 diabetes.

Obesity (Silver Spring). 2011 Jun;19(6):1200-4

Dose-dependent inhibition of the post-prandial glycaemic response to a standard carbohydrate meal following incorporation of alpha-cyclodextrin.

BACKGROUND: This study evaluated the dose-response effects of alpha-cyclodextrin, a cyclic oligosaccharide, on the glycemic and insulin emic responses to the consumption of a standard carbohydrate meal. METHODS: In a double-blind, randomised, cross-over design, 10 healthy subjects consumed boiled white rice containing 50 g of digestible carbohydrate to which 0 (control), 2, 5 or 10 g of alpha-cyclodextrin was added. Plasma glucose and insulin concentrations were determined prior to and for 2 h after consumption of each meal. RESULTS: The area under the plasma glucose curve was negatively related to the dose of alpha-cyclodextrin (r(2)=0.97, p=0.02), with the areas being
significantly reduced at the 5- and 10-gram doses compared with the control (p<0.05). alpha-Cyclodextrin did not affect the area under the plasma insulin curve (p=0.39). Higher doses of alpha-cyclodextrin resulted in greater satiety, but were associated with reduced palatability and an increased incidence of minor gastrointestinal complaints (stomach ache, nausea, bloating). CONCLUSION: alpha-Cyclodextrin reduces the glycemic response to a standard carbohydrate meal in a dose-dependent manner and may be useful as an ingredient for reducing the glycemic impact of such foods.

Ann Nutr Metab . 2006;50(2):108-14

A mixture of Salacia reticulata (Kotala himbutu) aqueous extract and cyclodextrin reduces body weight gain, visceral fat accumulation, and total cholesterol and insulin increases in male Wistar fatty rats.

This study examined the effects of a mixture of an aqueous extract of Salacia reticulata (Kotala himbutu) and cyclodextrin (SRCD) on various metabolic parameters and cecal fermentation in obese fa/fa male Wistar fatty rats, a model of type 2 diabetes mellitus. Wistar fatty rats were fed 0% (control group) or 0.2% SRCD-supplemented diets and weighed weekly. The plasma glucose, triacylglycerol, total cholesterol, insulin, and adiponectin concentrations were measured at weeks 0, 2, 4, and 5. SRCD supplementation suppressed the time-dependent increase in the plasma total cholesterol and insulin concentrations. After 6 weeks of a 0.2% SRCD-supplemented diet, the body weight gain, food intake, visceral fat mass, liver mass, and liver triacylglycerol content of the rats were significantly lower, whereas the plasma adiponectin concentrations were significantly higher than those of the control group. SRCD supplementation had no significant effect on plasma glucose and triacylglycerol concentrations. SRCD supplementation significantly increased cecum mass, whereas it significantly decreased the cecal butyrate and short-chain fatty acid (sum of the acetate, butyrate, and propionate) concentrations. All of the rats were subjected to an oral glucose tolerance test at the beginning of week 6. The area under the curve for insulin was significantly smaller with SRCD supplementation and showed no change in glucose tolerance compared to that of the control group. These results suggest that bioactive compounds in SRCD may suppress the development of type 2 diabetes mellitus by influencing glucose and lipid metabolism in male Wistar fatty rats and that SRCD may influence cecal fermentation.

Nutr Res . 2009 Jan;29(1):55-63

Effect of glucomannan on obese patients: a clinical study.

An eight-week double-blind trial was conducted to test purified glucomannan fiber as a food supplement in 20 obese subjects. Glucomannan fiber (from konjac root) or placebo was given in 1-g doses (two 500 mg capsules) with 8 oz water, 1 h prior to each of three meals per d. Subjects were instructed not to change their eating or exercise patterns. Results showed a significant mean weight loss (5.5 lbs) using glucomannan over an eight-week period. Serum cholesterol and low-density lipoprotein cholesterol were significantly reduced (21.7 and 15.0 mg/dl respectively) in the glucomannan treated group. No adverse reactions to glucomannan were reported.

Int J Obes. 1984;8(4):289-93

Lowering the glycemic index of white bread using a white bean extract.

BACKGROUND: Phase 2((R)) is a dietary supplement derived from the common white kidney bean (Phaseolus vulgaris). Phase 2 has been shown to inhibit alpha-amylase, the complex carbohydrate digesting enzyme, in vitro. The inhibition of alpha-amylase may result in the lowering of the effective Glycemic Index (GI) of certain foods. The objective of this study was to determine whether the addition of Phase 2 would lower the GI of a commercially available high glycemic food (white bread). METHODS: An open-label 6-arm crossover study was conducted with 13 randomized subjects. Standardized GI testing was performed on white bread with and without the addition of Phase 2 in capsule and powder form, each in dosages of 1500 mg, 2000 mg, and 3000 mg. Statistical analysis was performed by one-way ANOVA of all seven treatment groups using unadjusted multiple comparisons (t tests) to the white bread control.RESULTS: For the capsule formulation, the 1500 mg dose had no effect on the GI and the 2000 mg and 3000 mg capsule doses caused insignificant reductions in GI. For the powder, the 1500 mg and 2000 mg doses caused insignificant reductions in the GI, and the 3000 mg dose had a significant effect (-20.23 or 34.11%, p = 0.023) CONCLUSION: Phase 2 white bean extract appears to be a novel and potentially effective method for reducing the GI of existing foods without modifying their ingredient profile.

Nutr J. 2009 Oct 28;8:52

Phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats.

Phloridzin is the specific and competitive inhibition of sodium/glucose cotransporters in the intestine (SGLT1) and kidney (SGLT2). This property which could be useful in the management of postprandial hyperglycemia in diabetes and related disorders. Phloridzin is one of the dihydrochalcones typically contained in apples and in apple-derived products. The effect of phloridzin orally doses 5, 10, 20, and 40 mg/kg body weight on diabetes was tested in a streptozotocin-induced rat model of diabetes type 1. From beneficial effect of this compound is significant reduction of blood glucose levels and improve dyslipidemia in diabetic rats. As a well-known consequence of becoming diabetic, urine volume and water intake were significantly increased. Administration of phloridzin reduced urine volume and water intake in a dose-dependent manner. Phloretin decreases of food consumption, as well as a marked lowering in the weight. In conclusion, this compound could be proposed as an antihyperglycemic and antihyperlipidemic agent in diabetes and potential therapeutic in obesity.

Mol Biol Rep. 2012 May;39(5):5299-306

Supplementing transglucosidase with a high-fiber diet for prevention of postprandial hyperglycemia in streptozotocin-induced diabetic dogs.

Indigestible oligosaccharides have been shown to normalize blood glucose and insulin concentration thereby promoting good health and preventing diseases, such as diabetes. Transglucosidase (TG, alpha-glucosidase, enzyme code (EC) 3.2.1.20) is an enzyme capable of converting starch to oligosaccharides, such as iso-malto-oligosaccharides from maltose, via the action of amylase. The aim of this study was to evaluate whether oral administration of TG with maltose or dextrin is capable of reducing post-prandial serum glucose concentration in experimentally streptozotocin (STZ)-induced diabetic dogs fed on a high-fiber diet. Five healthy and five STZ-induced diabetic dogs were employed in this study. TG supplementation with dextrin or maltose had no detrimental effect in healthy dogs. In fact, TG and dextrin exhibited a flatlined serum glucose pattern, while reducing mean post-prandial serum insulin and glucose concentration as compared to control diet alone. When TG supplementation was tested in STZ-induced diabetic dogs under the context of a high fiber diet, a 13.8% and 23.9% reduction in mean glucose concentration for TG with maltose and dextrin, respectively was observed. Moreover, TG with dextrin resulted in a 13% lower mean post-prandial glucose concentration than TG with maltose, suggesting that dextrin may be a more efficient substrate than maltose when used at the same concentration (1 g/kg). Our results indicate that TG supplementation with diet can lead to lower postprandial glucose levels versus diet alone. However, the efficacy of TG supplementation may depend on the type of diet it is supplemented with. As such, TG administration may be useful for preventing the progression of diabetes mellitus and in its management in dogs.

Vet Res Commun. 2010 Feb;34(2):161-72

A novel strategy in production of oligosaccharides in digestive tract: prevention of postprandial hyperglycemia and hyperinsulinemia.

The aim of this study was to evaluate the effects of oral administration of transglucosidase (TG) on postprandial glucose concentrations in healthy subjects. A randomized placebo-controlled three-way crossover trial was separated by a washout period of more than 3 days. Twenty-one normal healthy volunteers, aged 30-61 years old (17 males and 4 females) were selected for this study. The subjects’ health was assessed as normal by pre-study screening. All subjects received 3 types of test meals (3 rice balls: protein, 14.4 g; fat, 2.1 g; and carbohydrate, 111 g: total energy, 522 kcal) with 200 ml water in which 0 mg, 150 mg, or 300 mg of TG was dissolved. Blood samples for estimating plasma glucose and insulin concentrations were collected before and every 30 min after the experiment. As compared to no TG treatment, TG administration tended to prevent a postprandial increase in plasma glucose (p = 0.069: 150 mg of TG vs control) but there were no significant difference among three groups. With regard to the 17 subjects who were suggested to have impaired glucose tolerance, TG significantly decreased the postprandial blood glucose (p<0.05: 150 mg and 300 mg of TG vs control) and marginally decreased insulin concentrations (p = 0.099: 300 mg of TG vs control). These results suggest that TG may be useful for preventing the progression of type 2 diabetes mellitus.

J Clin Biochem Nutr. 2007 Nov;41(3):191-6