Ali A. Moazzami

STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

Nuclear Magnetic Resonance–Based Metabolomics Enable Detection of the Effects of a Whole Grain Rye and Rye Bran Diet on the Metabolic Profile of Plasma in Prostate Cancer Patients

Prostate cancer (PC) is the most common cancer in the Western world and the second most important cancer causing male deaths, after lung cancer, in the United States and Britain. Lifestyle and dietary changes are recommended for men diagnosed with early-stage PC. It has been shown that a diet rich in whole grain (WG) rye reduces the progression of early-stage PC, but the underlying mechanism is not clear. This study sought to identify changes in the metabolic signature of plasma in patients with early-stage PC following intervention with a diet rich in WG rye and rye bran product (RP) compared with refined white wheat product (WP) as a tool for mechanistic investigation of the beneficial health effects of RP on PC progression. Seventeen PC patients received 485 g RP or WP in a randomized, controlled, crossover design during a period of 6 wk with a 2-wk washout period. At the end of each intervention period, plasma was collected after fasting and used for (1)H NMR-based metabolomics. Multilevel partial least squares discriminant analysis was used for paired comparisons of multivariate data. A metabolomics analysis of plasma showed an increase in 5 metabolites, including 3-hydroxybutyric acid, acetone, betaine, N,N-dimethylglycine, and dimethyl sulfone, after RP. To understand these metabolic changes, fasting plasma homocysteine, leptin, adiponectin, and glucagon were measured separately. The plasma homocysteine concentration was lower (P = 0.017) and that of leptin tended to be lower (P = 0.07) after RP intake compared to WP intake. The increase in plasma 3-hydroxybutyric acid and acetone after RP suggests a shift in energy metabolism from anabolic to catabolic status, which could explain some of the beneficial health effects of WG rye, i.e., reduction in prostate-specific antigen and reduced 24-h insulin secretion. In addition, the increase in betaine and N,N-dimethylglycine and the decrease in homocysteine show a favorable shift in homocysteine metabolism after RP intake.

1H NMR-based metabolomics studies on the effect of sesamin in Atlantic salmon (Salmo salar)

A (1)H NMR-based metabolomics approach was used to explore the impact of dietary sesamin on the liver and white muscle metabolic profile of Atlantic salmon (Salmo salar). Fish were fed diets containing different n-6/n-3 fatty acid ratios (V0.5 or V1) and sesamin contents [without (S0), low (SL) 1.16 g/kg feed, and high (SH) 5.8 g/kg feed] for 4 months. Liver and white muscle extracts of aqueous polar and chloroform lipid phases were collected. Multivariate data analyses (PCA and OPLS-DA) of liver chloroform phase showed that high levels of sesamin affected the metabolic profile impartially of the n-6/n-3 ratio. In the aqueous phase, the metabolome of liver and white muscle were affected in fish fed an n-6/n-3 ratio of 1.0 and 0.5, respectively. With high inclusion of sesamin, the levels of several metabolites (e.g. glucose, glycogen, leucine, valine, creatine, carnitine, lactate, nucleosides) were increased. These metabolites are mainly associated with energy metabolism, suggesting that high sesamin inclusion affects liver and white muscle metabolism in fish. This is consistent with lower body weights found in fish fed high sesamin content.

Sesame Seed Lignans: Potent Physiological Modulators and Possible Ingredients in Functional Foods & Nutraceuticals

Sesame seed contains very high levels (up to 2.5%) of furofuran lignans with beneficial physiological activities, mainly sesamin, sesamolin, and sesaminol glucosides. Reported activities of sesame seed lignans include inter alias modulation of fatty acid metabolism, inhibition of cholesterol absorption and biosynthesis, antioxidant and vitamin E-sparing effects, hypotensive effects, improvement of liver functions in connection with alcohol metabolism, and antiaging effects. This review comprehends patents pertinent to the preparations and uses of sesame seed lignans in health promotion.

Metabolomics reveals the metabolic shifts following an intervention with rye bread in postmenopausal women- a randomized control trial

BackgroundEpidemiological studies have consistently shown that whole grain (WG) cereals can protect against the development of chronic diseases, but the underlying mechanism is not fully understood. Among WG products, WG rye is considered even more potent because of its unique discrepancy in postprandial insulin and glucose responses known as the rye factor. In this study, an NMR-based metabolomics approach was applied to study the metabolic effects of WG rye as a tool to determine the beneficial effects of WG rye on human health.MethodsThirty-three postmenopausal Finnish women with elevated serum total cholesterol (5.0-8.5 mmol/L) and BMI of 20–33 kg/m2 consumed a minimum of 20% of their daily energy intake as high fiber WG rye bread (RB) or refined wheat bread (WB) in a randomized, controlled, crossover design with two 8-wk intervention periods separated by an 8-wk washout period. At the end of each intervention period, fasting serum was collected for NMR-based metabolomics and the analysis of cholesterol fractions. Multilevel partial least squares discriminant analysis was used for paired comparisons of multivariate data.ResultsThe metabolomics analysis of serum showed lower leucine and isoleucine and higher betaine and N,N-dimethylglycine levels after RB than WB intake. To further investigate the metabolic effects of RB, the serum cholesterol fractions were measured. Total- and LDL-cholesterol levels were higher after RB intake than after WB (p<0.05).ConclusionsThis study revealed favorable shifts in branched amino acid and single carbon metabolism and an unfavorable shift in serum cholesterol levels after RB intake in postmenopausal women, which should be considered for evaluating health beneficial effects of rye products.

Plant Sterols and Stanols as Cholesterol-Lowering Ingredients in Functional Foods

This article reviews developments related to the use of plant sterols and stanols as cholesterol-lowering ingredients in foods and nutraceuticals preparations. Plant sterols and stanols are extracted from the deodorizer distillates of vegetable oil refining and from tall oil, a by-product of paper pulping industry. Plant sterols/stanols inhibit cholesterol absorption possibly by competitively inhibiting its incorporation into the mixed micelles in the small intestine although other mechanisms can not be excluded. Daily consumption of 1-2 grams of plant sterols or stanols was shown to cause 10-20% reduction in low-density lipoprotein cholesterol (LDL cholesterol). Combinations of plant sterols/stanols with certain lipid-lowering ingredients were shown to potentate their cholesterol-lowering effects and, in some cases, add triacylglycerol-lowering effects. In this article, patents based information is also discussed.

Metabolomics Reveals Differences in Postprandial Responses to Breads and Fasting Metabolic Characteristics Associated with Postprandial Insulin Demand in Postmenopausal Women

Changes in serum metabolic profile after the intake of different food products (e.g., bread) can provide insight into their interaction with human metabolism. Postprandial metabolic responses were compared after the intake of refined wheat (RWB), whole-meal rye (WRB), and refined rye (RRB) breads. In addition, associations between the metabolic profile in fasting serum and the postprandial concentration of insulin in response to different breads were investigated. Nineteen postmenopausal women with normal fasting glucose and normal glucose tolerance participated in a randomized, controlled, crossover meal study. The test breads, RWB (control), RRB, and WRB, providing 50 g of available carbohydrate, were each served as a single meal. The postprandial metabolic profile was measured using nuclear magnetic resonance and targeted LC-mass spectrometry and was compared between different breads using ANOVA and multivariate models. Eight amino acids had a significant treatment effect (P < 0.01) and a significant treatment × time effect (P < 0.05). RWB produced higher postprandial concentrations of leucine (geometric mean: 224; 95% CI: 196, 257) and isoleucine (mean ± SD: 111 ± 31.5) compared with RRB (geometric mean: 165; 95% CI: 147, 186; mean ± SD: 84.2 ± 22.9) and WRB (geometric mean: 190; 95% CI: 174, 207; mean ± SD: 95.8 ± 17.3) at 60 min respectively (P < 0.001). In addition, 2 metabolic subgroups were identified using multivariate models based on the association between fasting metabolic profile and the postprandial concentration of insulin. Women with higher fasting concentrations of leucine and isoleucine and lower fasting concentrations of sphingomyelins and phosphatidylcholines had higher insulin responses despite similar glucose concentration after all kinds of bread (cross-validated ANOVA, P = 0.048). High blood concentration of branched-chain amino acids, i.e., leucine and isoleucine, has been associated with the increased risk of diabetes, which suggests that additional consideration should be given to bread proteins in understanding the beneficial health effects of different kinds of breads. The present study suggests that the fasting metabolic profile can be used to characterize the postprandial insulin demand in individuals with normal glucose metabolism that can be used for establishing strategies for the stratification of individuals in personalized nutrition.

Characterization and Analysis of Sesamolinol Diglucoside in Sesame Seeds

A new lignan glucoside was isolated from defatted sesame seed flour and its structure was established as sesamolinol diglucoside [2-(3-methoxy-4-(O-β-D-glucopyranosyl (1→6)-O-β-D-glucopyranoside)phenoxyl)-6-(3,4-methylenedioxyphenyl)-cis-3,7-dioxabicyclo-(3.3.0)-octane] by mass and nuclear magnetic resonance spectroscopy. A quantitative analysis of 65 sesame seed samples showed that this sesamolinol diglucoside ranged from <5 to 232 mg/100 g of seeds (98±57 mg/100 g) with no difference between white and black sesame seeds.

Changes in the metabolic profile of rat liver after α‐tocopherol deficiency as revealed by metabolomics analysis

Metabolomics is an approach in which the profiles of metabolites in different tissues and/or biofluids are investigated to understand the changes induced following a modulation. We used this approach to investigate the biochemical effects of α‐tocopherol in the liver using a rat model. Rats (21‐day‐old) were fed either an α‐tocopherol‐sufficient control (n = 10) or an α‐tocopherol‐deficient (n = 10) diet for 2 months before sacrifice. Livers were homogenized in methanol–chloroform–water (3 : 1 : 1, v/v/v), and the polar phase extracts of the liver samples were analyzed using 1H NMR. Multivariate statistical analysis of the data was performed using principal component analysis and orthogonal partial least squares‐discriminant analysis. Identification of 1H NMR signals was performed primarily using the Human Metabolome Database, Biological Magnetic Resonance Data Bank and previous literature, and confirmed by spiking with metabolites and applying two‐dimensional NMR. The statistical analysis revealed that α‐tocopherol deficiency caused an increase in carnitine, choline, L‐valine, L‐lysine, tyrosine and inosine content and a reduction in glucose and uridine 5′‐monophosphate content. Changes in carnitine and glucose suggest a possible shift in energy metabolism. Copyright

High-fiber rye diet increases ileal excretion of energy and macronutrients compared with low-fiber wheat diet independent of meal frequency in ileostomy subjects.

Background Whole-grain foods and cereal dietary fiber intake is associated with lower body weight. This may partly result from lower energy utilization of high-fiber diets. Objective In the present study, the impact on ileal excretion of energy and macronutrients in response to a rye bread high-fiber diet compared to a refined wheat low-fiber diet was investigated. Furthermore, the effect of meal frequency on apparent absorption of nutrients was studied for the first time. Design Ten participants that had undergone ileostomy consumed standardized iso-caloric diets, including low-fiber wheat bread (20 g dietary fiber per day) for 2 weeks followed by high-fiber rye bread (52 g dietary fiber per day) for 2 weeks. The diets were consumed in an ordinary (three meals per day) and a nibbling (seven meals per day) meal frequency in a cross-over design. Ileal effluents were collected during 24 h at the third day of each of the four dietary periods and analyzed for gross energy and nutrient contents. Results The results showed that intake of rye bread high-fiber diet compared to the refined wheat low-fiber diet caused an increase in ileal excretion of energy and macronutrients. The effect was independent of meal frequency. This suggests that a high intake of rye may result in lower availability of macronutrients for small intestinal digestion and absorption. A regular intake of rye may therefore have implications for weight management.