Plant sterols may induce a Th1 shift in humans. However, whether plant stanols have similar effects as well as the underlying mechanism are unknown. We have now shown that - like sitosterol - sitostanol, which are both 4-desmethylsterols, induce a Th1 shift, when added in vitro at physiological concentrations to human PBMCs. This conclusion was based on a higher IFNgamma production, with no change in the production of IL-4 and IL-10. Alpha-amyrin, a 4.4-dimethylsterol, had comparable effects. Since 4.4-dimethylsterols cannot activate transcription factor LXR, this finding indicates that LXR activation was not involved. Sitosterol and sitostanol did not alter the production of IL-12 and IL-18 in PBMCs as well as in monocyte derived U937 cells, suggesting that plant sterols directly affect T-helper cells, without activating APCs. However, in PBMCs treated with a TLR2 blocker (T2.5), IFNgamma production was completely inhibited, while blocking TLR4 with HTA125 had no such effect. To confirm these findings, PBMCs from TLR2-/- mice were cultured in the presence of sitosterol and sitostanol. In these cells, no Th1 shift was observed. Our results therefore indicate that TLR2 activation is essential to induce a Th1 shift in human PBMCs by plant stanols and plant sterols.

Mushrooms are known for their immune-modulating and anti-tumour properties. The polysaccharide fraction, mainly beta-glucans, is responsible for the immune-modulating effects. Fungal beta-glucans have been shown to activate leukocytes, which depend on structural characteristics of beta-glucans. As edible mushrooms come in contact with the intestinal immune system, effects on enterocytes are also interesting. Our aim was to evaluate the effect of mushroom polysaccharide extracts varying in beta-glucan structure on nitric oxide production by bone marrow-derived macrophages (BMMs) from mice and on nuclear factor-kappaB transactivation in human intestinal Caco-2 cells. We demonstrated that extracts from Agaricus bisporus stimulated nitric oxide production by BMM, whereas extracts from Coprinus comatus and spores of Ganoderma lucidum had only minor effects. Furthermore, extracts of A. blazei Murill and Phellinus linteus had no effect at all. Almost all mushroom extracts lowered nuclear factor-kappaB transactivation in Caco-2 cells. Structural analysis of A. bisporus compared with A. blazei Murill suggests that branching of the beta-glucan chain is essential for immune-stimulating activity. In conclusion, extracts from A. bisporus activate BMM, without activating enterocytes. These characteristics make A. bisporus an attractive candidate as a nutritional compound to stimulate the immune response in depressed states of immunity.

BACKGROUND: Many studies on the health effects of the glycemic index (GI) are confounded by differences in the intakes of other macronutrients and fibre. Little data exist about the within- and between-subject variability of the GI. OBJECTIVE: Our objectives were therefore (i) to calculate the GI of eight commonly used food products with similar macronutrient and fibre composition, but with different sources of carbohydrates (ii) to examine the inter- and intra-individual variability of the incremental area under the curve (iAUC) after consuming the reference solution (iii) to compare the effect of three different methods on 2-h postprandial blood glucose responses. DESIGN: Four groups of 10 healthy subjects consumed in random order the increased (iGI) and decreased GI (dGI) variants and twice a glucose solution. All products consisted of 25g available carbohydrates (CHO). For the fruit drink, glucose values were simultaneously analyzed using venous and capillary blood samples, and by using a continuous glucose monitoring system (CGMS). RESULTS: The GIs for increased and decreased variants were (mean+/-standard error of the mean (SEM)) 69+/-15 and 40+/-4 for bread, 86+/-14 and 48+/-8 for fruit drink, 51+/-12 and 20+/-4 for cake, and 63+/-17 and 37+/-10 for cookie. The inter- and intra-individual coefficient of variation (CV) of the iAUCs of the reference solution was large and varied respectively between 13 and 38%, and between 33 and 80%. CONCLUSIONS: These data suggest that the GI is difficult to use at the individual level.

AbstractSkeletal muscle triglyceride accumulation is associated with insulin resistance in obesity. Recently, it has been suggested that alpha lipoic acid (ALA) improves insulin sensitivity by lowering triglyceride accumulation in non-adipose tissues via activation of skeletal muscle AMP-activated protein kinase (AMPK). We examined whether chronic ALA supplementation prevents muscular lipid accumulation that is associated with high-fat diets via activation of AMPK. In addition, we tested if ALA supplementation was able to improve insulin sensitivity in rats fed low- and high-fat diets.Supplementing male Wistar rats with 0.5% ALA for eight weeks significantly reduced body weight, both on low- and high-fat diets (-24% LFD+ALA vs. LFD, p<0.01, and -29% HFD+ALA vs. HFD, p<0.001). Oil red O lipid staining revealed a three-fold higher lipid content in skeletal muscle after HFD compared to LFD and ALA-supplemented groups (p<0.05). ALA improved whole body glucose tolerance ( approximately 20% lower total AUC in ALA supplemented groups vs. controls, p<0.05). These effects were not mediated by increased muscular AMPK activation or ALA-induced improvement of muscular insulin sensitivity. To conclude, the prevention of high-fat diet-induced muscular lipid accumulation and the improved whole body glucose tolerance are likely secondary effects due to the anorexic nature of ALA.

Recent animal and human studies have shown that plant sterols and stanols, which are used as functional food ingredients to lower increased LDL cholesterol concentrations, pass the blood-brain barrier. Whether this affects neurocognitive functioning and mental well-being in humans has, to our knowledge, never been investigated. The aim of the present study was therefore to examine the effects of long-term plant sterol or stanol consumption on neurocognitive functioning and mood in a randomized, double-blind, placebo-controlled dietary intervention trial. To this end, hypercholesterolemic individuals, aged 43-69 y, receiving stable statin treatment were randomly assigned to an 85-wk supplementation with margarines enriched with plant sterol esters (2.5 g/d), plant stanol esters (2.5 g/d), or placebo. At baseline and at the end of the intervention period, all participants underwent a cognitive assessment. In addition, subjective cognitive functioning and mood were assessed by means of questionnaires (Cognitive Failure Questionnaire and depression subscale of the Symptom Checklist 90, respectively). Long-term supplementation with plant sterol or stanol esters did not affect cognitive performance (memory, simple information processing speed, complex information processing speed, Letter-Digit Substitution test performance), subjective cognitive functioning, or mood. In conclusion, the present results indicate that long-term use of plant sterols or stanols at recommended intakes of 2.5 g/d does not affect neurocognitive functioning or mood in hypercholesterolemic individuals receiving statin treatment.

BACKGROUND: Increasing HDL cholesterol concentrations by stimulating de-novo apolipoprotein A-I (apoA-I) production in the liver and/or in the small intestine is a potential strategy to reduce coronary heart disease risk. Although there is quite some knowledge concerning regulatory effects in the liver, less is known concerning potential agents that could elevate de-novo apoA-I production in the small intestine. METHODS: Therefore, we compared side-by-side effects of various peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, retinoid-X-receptor alpha, and farnesoid-X-receptor agonists on de-novo apoA-I production in differentiated CaCo-2 and HepG2 cells. RESULTS: For PPARa agonists, we showed that GW7647 elevated apoA-I concentrations in the medium of both cell models, whereas WY14643 elevated only de-novo apoA-I concentrations in differentiated CaCo-2 cells. Unexpectedly, fenofibric acid lowered apoA-I medium concentrations in both cell lines, which could not be explained by a lack of PPAR transactivation or a lack of retinoid-X-receptor a activation. For farnesoid-X-receptor agonists, chenodeoxycholic acid strongly reduced apoA-I concentrations both in differentiated CaCo-2 and HepG2 cells, whereas GW4064 and taurocholate only lowered apoA-I in CaCo-2 cells (GW4064) or in HepG2 cells (taurocholate). However, overall effects of all individual components on apoA-I production in differentiated CaCo-2 and HepG2 cells were highly correlated (r = 0.68; P = 0.037; N=9). CONCLUSION: We conclude that differentiated CaCo-2 cells are suitable models to study de-novo small intestinal apoA-I production in vitro enabling the possibility to screen for potential bioactive dietary components. This cell model may also determine small-intestinal-specific effects, as some discrepancy was found between both cell models.

We evaluated the effects of 2 commonly available strategies (plant stanol ester drink and 10 mg simvastatin) on coronary heart disease (CHD) risk variables in participants with metabolic syndrome. Metabolic syndrome patients are at increased risk to develop CHD, partly due to high triacylglycerol (TAG) and low HDL cholesterol (HDL-C) concentrations and a low-grade inflammatory profile. Effects of plant stanol esters on TAG concentrations in these participants are unknown. After a 3-wk run-in period in which individuals consumed placebo yogurt drinks and placebo capsules, participants were randomly divided into 4 groups: placebo (n = 9), simvastatin + placebo drink (n = 10), placebo + stanol drink (n = 9), and simvastatin + stanol drink (n = 8). After 9 wk, we evaluated the effects on serum lipids, low-grade inflammation, and endothelial dysfunction markers. In metabolic syndrome patients, stanol esters (2.0 g/d), simvastatin, or the combination lowered non-HDL-C by 12.8%(P = 0.011), 30.7%(P < 0.001), and 35.4%(P < 0.001), respectively, compared with placebo. TAG were lowered by 27.5%(P = 0.044), 21.7%(P = 0.034), and 32.7%(P < 0.01), respectively. The total-:HDL-C ratio was significantly lowered in all 3 intervention groups. We found no treatment effects on the apolipoprotein CII:CIII ratio, cholesterol ester transfer protein mass, FFA concentrations, and markers for low-grade inflammation or endothelial dysfunction. This study shows that in metabolic syndrome patients, plant stanol esters lower not only non-HDL-C, but also TAG. Effects on TAG were also present in combination with statin treatment, illustrating an additional benefit of stanol esters in this CHD risk population.

The metabolic syndrome is an important risk factor for type 2 diabetes mellitus and CVD. Epidemiological studies have now suggested protective effects of dairy product consumption on the development of this syndrome. Here we review the physiological effects and possible mechanisms involved of three main dairy constituents (Ca, protein, fat) on important components of the metabolic syndrome. Ca supplements improve the serum lipoprotein profile, particularly by decreasing serum total and LDL-cholesterol concentrations. They also lower systolic and diastolic blood pressure. Insufficient evidence exists for a significant role of Ca supplements or dairy in body-weight management. Effects of Ca may be related to intestinal binding to fatty acids or bile acids, or to changes in intracellular Ca metabolism by suppressing calciotropic hormones. Dietary proteins may increase satiety in both the short and longer term, which may result in a reduced energy intake. They have also been reported to improve the serum lipoprotein profile as compared with carbohydrates. Dairy proteins are precursors of angiotensin-I-converting enzyme-inhibitory peptides, which may lower blood pressure. Such effects, however, have inconsistently been reported in human studies. Finally, conjugated linoleic acid, which effectively lowers body weight in animals, has no such effect in humans in the quantities provided by dairy products. To reduce the intake of SFA, the consumption of low-fat instead of high-fat dairy products is recommended. In conclusion, more research is warranted to better understand the physiological effects and the mechanisms involved of dairy products in the prevention and treatment of the metabolic syndrome.

Beneficial effects of low glycemic index (GI) diets in rodents have been studied using healthy low-fat diets, while the effects might be different on high-fat diets inducing progression of insulin resistance. We fed C57BL/6J male mice high-fat low/high-GI (LGI/HGI) diets for 13 wk. Glucose and insulin tolerance and serum substrates, including adipokines, were measured longitudinally. The LGI group showed a significantly higher glucose tolerance from wk 2 onwards, which was supported by lower serum insulin and free fatty acids levels at 8 wk, and a tendency for lower leptin levels, while resistin levels remained similar. At 11 wk, when differences in serum resistin started to increase, differences in serum insulin were diminished. Although food intake was similar throughout the study, body weights and epididymal adipose tissue mass became significantly lower in the LGI group at necropsy. Several serum substrates and adipose tissue leptin mRNA levels, as analyzed by Q-PCR, were, again, significantly lower, whereas adiponectin mRNA levels were higher. Taken together, an LGI high-fat diet maintains higher glucose tolerance and insulin sensitivity via adipose tissue modulation solely because of a difference in the type of carbohydrate, supporting a nutritional approach in the fight against insulin resistance.-Van Schothorst, E. M., Bunschoten, A., Schrauwen, P., Mensink, R. P., Keijer, J. Effects of a high-fat, low versus high glycemic index diet: retardation of insulin resistance involves adipose tissue modulation.