Abstract The evolution of the human diet over the past 10,000 years from a Paleolithic diet to our current modern pattern of intake has resulted in profound changes in feeding behavior. Shifts have occurred from diets high in fruits, vegetables, lean meats, and seafood to processed foods high in sodium and hydrogenated fats and low in fiber. These dietary changes have adversely affected dietary parameters known to be related to health, resulting in an increase in obesity and chronic disease, including cardiovascular disease (CVD), diabetes, and cancer. Some intervention trials using Paleolithic dietary patterns have shown promising results with favorable changes in CVD and diabetes risk factors. However, such benefits may be offset by disadvantages of the Paleolithic diet, which is low in vitamin D and calcium and high in fish potentially containing environmental toxins. More advantageous would be promotion of foods and food ingredients from our ancestral era that have been shown to possess health benefits in the form of functional foods. Many studies have investigated the health benefits of various functional food ingredients, including omega-3 fatty acids, polyphenols, fiber, and plant sterols. These bioactive compounds may help to prevent and reduce incidence of chronic diseases, which in turn could lead to health cost savings ranging from $2 to $3 billion per year as estimated by case studies using omega-3 and plant sterols as examples. Thus, public health benefits should result from promotion of the positive components of Paleolithic diets as functional foods.

PURPOSE OF REVIEW: To examine experimental evidence that has examined association of phytosterols and the reduction of the risk of cardiovascular disease and cancer. RECENT FINDINGS: Phytosterols exist as naturally occurring plant sterols that are present in the nonsaponifiable fraction of plant oils. Phytosterols are plant components that have a chemical structure similar to cholesterol except for the addition of an extra methyl or ethyl group; however, phytosterol absorption in humans is considerably less than that of cholesterol. In fact, phytosterols reduce cholesterol absorption, although the exact mechanism is not known, and thus reduce circulating levels of cholesterol. The efficacy of phytosterols as cholesterol-lowering agents have been shown when incorporated into fat spreads as well as other food matrices. In addition, phytosterols have been combined with other beneficial dietary components including fish and olive oils, psyllium and beta-glucan to enhance their effect on risk factors of cardiovascular disease. Phytosterols appear not only to play an important role in the regulation of cardiovascular disease but also to exhibit anticancer properties. A side effect associated with the consumption of phytosterols is that they reduce the blood levels of carotenoid. Nevertheless, it has been suggested that compensation for this impact on serum carotenoid levels can occur either by increasing the intake of carotenoid-rich foods or by taking supplements containing these carotenoids. SUMMARY: Dietary phytosterols appear to play an important role in the regulation of serum cholesterol and to exhibit anticancer properties.

BACKGROUND: Consumption of plant sterols has been reported to reduce low density lipoprotein (LDL) cholesterol concentrations by 5-15%. Factors that affect plant sterol efficacy are still to be determined. OBJECTIVES: To more precisely quantify the effect of plant sterol enriched products on LDL cholesterol concentrations than what is reported previously, and to identify and quantify the effects of subjects' characteristics, food carrier, frequency and time of intake on efficacy of plant sterols as cholesterol lowering agents. DESIGN: Fifty-nine eligible randomized clinical trials published from 1992 to 2006 were identified from five databases. Weighted mean effect sizes were calculated for net differences in LDL levels using a random effect model. RESULTS: Plant sterol containing products decreased LDL levels by 0.31 mmol/L (95% CI,-0.35 to -0.27, P=< 0.0001) compared with placebo. Between trial heterogeneity was evident (Chi-square test, P =<0.0001) indicating that the observed differences between trial results were unlikely to have been caused by chance. Reductions in LDL levels were greater in individuals with high baseline LDL levels compared with those with normal to borderline baseline LDL levels. Reductions in LDL were greater when plant sterols were incorporated into fat spreads, mayonnaise and salad dressing, milk and yoghurt comparing with other food products such as croissants and muffins, orange juice, non-fat beverages, cereal bars, and chocolate. Plant sterols consumed as a single morning dose did not have a significant effect on LDL cholesterol levels. CONCLUSION: Plant sterol containing products reduced LDL concentrations but the reduction was related to individuals' baseline LDL levels, food carrier, and frequency and time of intake.

Plant sterols are plant components that have a chemical structure similar to cholesterol except for the addition of an extra methyl or ethyl group; however, plant sterol absorption in humans is considerably less than that of cholesterol. In fact, plant sterols reduce cholesterol absorption and thus reduce circulating levels of cholesterol. Earlier studies that have tested the efficacy of plant sterols as cholesterol-lowering agents incorporated plant sterols into fat spreads. Later on, plant sterols were added to other food matrices, including juices, nonfat beverages, milk and yogurt, cheese, meat, croissants and muffins, and cereal and chocolate bars. The beneficial physiologic effects of plant sterols could be further enhanced by combining them with other beneficial substances, such as olive and fish oils, fibers, and soy proteins, or with exercise. The addition of plant sterols to the diet is suggested by health experts as a safe and effective way to reduce the risk of coronary heart disease.

OBJECTIVE: Plant sterols (PS) consumed as a snack may not have the same cholesterol-lowering potential as when consumed with a meal due to poor solubilization. It was hypothesized that the consumption of a single dose, low-fat yogurt rich in PS (1.6 g/d) with a meal over an afternoon snack will lead to favourable changes in plasma lipids, plasma PS concentrations, and cholesterol synthesis without negatively affecting alpha-tocopherol or carotenoids levels. METHODS: Twenty-six hyperlipidemic males and females completed the randomized trial of three phases (control, single PS dose consumed with a meal, or single PS dose as an afternoon snack) while consuming controlled, low-fat diets. Plasma lipids, cholesterol synthesis rates, plasma PS and serum fat-soluble antioxidants were measured at baseline and after 4 weeks. RESULTS: Endpoint total cholesterol (TC) levels after the PS snack phase were decreased (p = 0.04)(5.30 +/- 0.2 mmol/L) compared to the control phase (5.53 +/- 0.2 mmol/L). However, endpoints for TC (5.37 +/- 0.2 mmol/L) for PS dose with a meal were comparable to control phase. Low-density lipoprotein-cholesterol tended to be different (p = 0.06) at the end of the intervention phases (3.51 +/- 0.1, 3.43 +/- 0.1, and 3.33 +/- 0.1 mmol/L; control, meal and snack, respectively). Cholesterol fractional synthesis rates were higher (p = 0.007) by 25.8% and 19.5% at the end of the snack and meal phases, respectively, compared with the control phase. Plasma campesterol and beta-sitosterol concentrations, adjusted for TC, were higher (p < 0.01) in the snack phase (2.30 +/- 0.3 and 0.54 +/- 0.1 micromol/mmol, respectively) and in the meal phase (2.00 +/- 0.3 and 0.51 +/- 0.1 micromol/mmol, respectively) when compared to the control phase (1.81 +/- 0.3 and 0.40 +/- 0.1 micromol/mmol, respectively). No changes in alpha-tocopherol or carotenoids levels were detected after adjusting for TC, for all phases. CONCLUSION: These results indicate that a single dose of PS in low-fat yogurt, provided as a snack, lowers cholesterol levels but does not alter fat-soluble vitamin or carotenoid concentrations in hyperlipidemic participants.

Plant sterol (PS) consumption decreases low-density lipoprotein cholesterol (LDL-C) levels; however, high variability of responsiveness of lipid levels to PS intervention has been observed. We hypothesized that common single-nucleotide polymorphisms (SNPs) in the genes for the ATP binding cassette proteins G5 (ABCG5) and G8 (ABCG8), Niemann-Pick C1-like 1 (NPC1L1), or other proteins of the cholesterol pathway, would underline inter-individual variations in response to PS. Twenty-six hyperlipidemic subjects completed a randomized trial of 3 PS phases and a control phase. Three non-responders were identified who failed on 3 consecutive occasions to decrease either total cholesterol or LDL-C level vs. control. It was observed that after 3 PS phases compared with a control phase, cholesterol absorption changed to a lesser degree (-7.7%+/- 10.8%) in the non-responders than in the top 3 responders (-22.1%+/- 8.8%); however, cholesterol synthesis rates did not differ between sub-groups. No common polymorphisms in ABCG8, ABCG5, or NPC1L1 were demonstrated between the 3 top responders and the non-responders. Yet, 1 non-responsive subject did demonstrate a rare SNP in NPC1L1. Results indicate PS intake did not decrease cholesterol absorption rates to the same degree in certain subjects, possibly clarifying the inter-individual variability in the cholesterol-lowering effect; hence, this work should be expanded.

Plant sterols (PSs) reduce plasma total and low-density lipoprotein cholesterol (LDL-C) levels by reducing cholesterol absorption; however, it is not known whether the level of dietary cholesterol intake has an impact on the efficacy of PSs on blood lipids. The purpose of this study was to determine the effect of high vs low dietary cholesterol levels on the lipid-lowering efficacy of free PSs. The study was a semirandomized, double-blind, crossover trial consisting of four 28-day feeding phases each separated by a 4-week washout period. Otherwise healthy hypercholesterolemic subjects (n = 22) consumed each of (a) low-cholesterol control (C(-)S(-)),(b) high-cholesterol control (C(+)S(-)),(c) 22 mg PSs per kilogram of body weight with a low-cholesterol diet (C(-)S(+)), and (d) 22 mg PSs per kilogram of body weight with a high-cholesterol diet (C(+)S(+)). Blood was drawn on the first and last 2 days of each phase to measure plasma total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triacylglycerols as well as plasma campesterol and beta-sitosterol concentrations. Dietary cholesterol had no effect on PS efficacy as a cholesterol-lowering agent because no interaction was found between the 2 factors. However, dietary cholesterol and PS intake had significant independent effects on plasma total cholesterol, LDL-C, and high-density lipoprotein cholesterol levels. beta-Sitosterol levels in plasma increased (P <.0001) as a result of PS supplementation. Data from the present study indicate that, although PSs and dietary cholesterol exert independent effects on plasma cholesterol, PS efficacy is not affected by varying levels of cholesterol intake.

Recommendations for decreasing the risk of developing cardiovascular disease include increasing the intake of plant sterols and fish oil. The cholesterol-lowering action of plant sterols, when provided in a fish-oil fatty acids vehicle, remains to be investigated in humans. A randomized, crossover-feeding, single-blind trial was conducted in 30 subjects with mild-to-moderate hypercholesterolemia to study the effects on plasma lipids of 2 novel forms of plant sterols: those combined with, or esterified to, fish-oil fatty acids. The treatments were margarine (control), free plant sterols, plant sterols esterified to fatty acids from sunflower oil, plant sterols esterified to very long-chained fatty acids from fish oil, and plant sterols combined with the same amount of very long-chained fatty acids from fish oil. Each sterol-containing food (1.0-1.8 g plant sterols/d) was consumed for 29 d as a single dose with breakfast under staff supervision. Compared with the control treatment, none of the plant sterol preparations reduced plasma total cholesterol or LDL cholesterol, triacylglycerol, apolipoprotein A-I, apolipoprotein B, lipoprotein (a), or C-reactive protein concentration. Relative to the control phase, all plant sterols treatment increased the plasma HDL cholesterol concentration (P < 0.05) by approximately 8%. In conclusion, because standard forms of plant sterols did not reduce plasma cholesterol concentrations, the efficacy of the new formulation of plant sterols cannot be confirmed from the present study design, where plant sterols were given as a single morning dose.

GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe that GMX1778 is a potent and specific inhibitor of the nicotinamide adenine dinucleotide (NAD(+)) biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD(+) turnover which makes NAD(+) modulation an attractive target for anticancer therapy. GMX1778 selectively inhibits NAMPT which blocks the production of NAD(+) and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA) which permits NAD(+) repletion via nicotinic acid phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that a high frequency of glioblastomas, neuroblastomas and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be extended in animals bearing NAPRT1-deficient tumors by co-administration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers.

Dietary energy restriction (ER) offers certain health benefits, particularly when ER is controlled through manipulation of dietary fats. Our hypothesis is that cellular immunity is modulated by dietary ER. Furthermore, we believe that the immune response may differ between spleen and colon because their lymphatic and vascular organization is different. The objective of the study was to test this hypothesis by determining the effects of dietary ER through manipulation of energy intake from high-fat (HF) diets on the expression and frequency of the CD4(+)(T-helper/T-inducer) and CD8(+)(T-cytotoxic/T-suppressor) cells, CD45RA (B-cell-specific marker), and immunoglobulins (Ig) A-, G-, and M-bearing cells in spleen and colon in rats by immunohistochemical method. Rats fed the HF diet had a significantly (P <.05) reduced number of immune cells as compared with those fed ER diets. Energy-restricted diet-fed rats showed higher (P <.05) numbers of CD4(+), CD8(+), IgA, IgM, IgG, and CD45RA cells in spleen and CD4(+), IgA, and CD45RA cells in colonic lamina propria. The IgA-containing cells were markedly higher in the colon compared with the spleen. No change occurred in the number of IgM- and IgG-containing cells in colonic tissues between groups, except for the 20% ER group where IgM-labeled cells were higher (P <.05) compared with HF and 40% ER groups. These findings suggest that ER may modulate adaptive immune function and that CD4(+) and IgA cells may serve as biological indicators for dietary energy-modulated immunoresponse in spleen and colon, respectively.

The proportion of elderly is growing worldwide. This trend is in parallel to an increase in diseases, such as cardiovascular disease (CVD). Plant sterols and stanols (PS) consumption is known to decrease low-density lipoprotein-cholesterol (LDL-C) levels by 5-15%, and thus lower CVD risk. Yet, the effect of PS on LDL-C levels differs between individuals. Furthermore, PS have recently been investigated for the prevention of other age-related diseases. The objective of this review is to examine the benefits of PS on CVD as well as ageing-associated diseases. PS have the ability to significantly lower LDL-C; yet, the large inter-individual variability in the lowering of LDL-C may be due to subject characteristics, food matrix of PS, dose of PS, dietary background, frequency of intake of PS, the additive effect of other foods or drugs, as well as genetic factors. Further, PS may also have other potential beneficial effects including anti-atherogenic, anti-inflammatory, antioxidant and anti-cancer activities. Overall, dietary intervention strategies, such as incorporating PS into a healthy diet, should be recommended and implemented in older adult populations in order to prevent ageing-associated diseases and hence promote healthy ageing.

BACKGROUND: Plant sterols are an important but underused dietary component in the treatment of elevated blood cholesterol. OBJECTIVE: This review discusses the background to plant sterol use and reviews evidence about its use in clinical practice. DISCUSSION: When consumed in the recommended amounts, sterols alone decrease low density lipoprotein cholesterol; in combination with other dietary changes, low density lipoprotein can be further lowered. Most patients, whether they are on cholesterol lowering drugs or not, would benefit from using plant sterols, which are now available in milk and yoghurt as well as spreads. In animal models, plant sterols have been shown to reduce atherosclerosis despite an elevation in the blood level, however there is no hard end point data for this in humans.

Several studies have shown that increased levels of low-density lipoprotein (LDL) cholesterol predict cardiovascular events. The Adult Treatment Panel II (ATP II) introduced the principle of therapeutic lifestyle changes, including plant sterols/stanols for the management of LDL cholesterol. Plant sterols and stanols in fat matrices effectively lower LDL cholesterol levels in hypercholesterolemic, diabetic, and healthy human volunteers. Recent studies also show that sterols (2 g/d) lower LDL cholesterol even when incorporated in nonfat matrices. In addition, they may reduce biomarkers of oxidative stress and inflammation. Plant sterols and stanols exert their hypocholesterolemic effects possibly by interfering with the uptake of both dietary and biliary cholesterol from the intestinal tract. Present evidence is accumulating to promote their use for lowering LDL cholesterol levels, as a first line of therapy (as well as adjunctive therapy) in patients on statin therapy.

Plant sterols (PS) are minor lipid components of plants, which may have potential health benefits, mainly based in their cholesterol-lowering effect. The aim of this study was to determine the composition and content of PS in plant-based foods commonly consumed in Spain and to estimate the PS intake in the Spanish diet. For this purpose, the determination of PS content, using a modern methodology to measure free, esterified, and glycosidic sterol forms, was done. Second, an estimation of the intake of PS, using the Spanish National Food Consumption data, was made. The daily intake per person of PS-campesterol, beta-sitosterol, stigmasterol, and stigmastanol-in the Spanish diet was estimated at 276 mg, the largest component being beta-sitosterol (79.7%). Other unknown compounds, tentatively identified as PS, may constitute a considerable potential intake (99 mg). When the daily PS intake among European diets was compared in terms of campesterol, beta-sitosterol, stigmasterol, and stigmastanol, the PS intake in the Spanish diet was in the same range of other countries such as Finland (15.7% higher) or The Netherlands (equal). However, some qualitative differences in the PS sources were detected, that is, the predominant brown bread and vegetable fat consumption in the northern diets versus the white bread and vegetable oil consumption in the Spanish diet. These differences may help to provide a link between the consumption of PS and healthy effects of the diet.