European Journal of Nutrition (v.51, #1)

Although carnitine is best known for its role in the import of long-chain fatty acids (acyl groups) into the mitochondrial matrix for subsequent β-oxidation, carnitine is also necessary for the efflux of acyl groups out of the mitochondria. Since intracellular accumulation of acyl-CoA derivatives has been implicated in the development of insulin resistance, carnitine supplementation has gained attention as a tool for the treatment of insulin resistance. More recent studies even point toward a causative role for carnitine insufficiency in developing insulin resistance during states of chronic metabolic stress, such as obesity, which can be reversed by carnitine supplementation.The present review provides an overview about data from both animal and human studies reporting effects of either carnitine supplementation or carnitine deficiency on parameters of glucose homeostasis and insulin sensitivity in order to establish the less well-recognized role of carnitine in regulating glucose homeostasis.Carnitine supplementation studies in both humans and animals demonstrate an improvement of glucose tolerance, in particular during insulin-resistant states. In contrast, less consistent results are available from animal studies investigating the association between carnitine deficiency and glucose intolerance. The majority of studies dealing with this question could either find no association or even reported that carnitine deficiency lowers blood glucose and improves insulin sensitivity.In view of the abovementioned beneficial effect of carnitine supplementation on glucose tolerance during insulin-resistant states, carnitine supplementation might be an effective tool for improvement of glucose utilization in obese type 2 diabetic patients. However, further studies are necessary to explain the conflicting observations from studies dealing with carnitine deficiency.
Keywords: Carnitine; Glucose homeostasis; Insulin sensitivity; Type 2 diabetes

Nutrition issues in Codex: health claims, nutrient reference values and WTO agreements: a conference report by Peter J. Aggett; John Hathcock; David Jukes; David P. Richardson; Philip C. Calder; Heike Bischoff-Ferrari; Theresa Nicklas; Stefan Mühlebach; Oran Kwon; Janine Lewis; Maurits J. F. Lugard; Peter Prock (1-7).
Codex documents may be used as educational and consensus materials for member governments. Also, the WTO SPS Agreement recognizes Codex as the presumptive international authority on food issues. Nutrient bioavailability is a critical factor in determining the ability of nutrients to provide beneficial effects. Bioavailability also influences the quantitative dietary requirements that are the basis of nutrient intake recommendations and NRVs.Codex, EFSA and some national regulatory authorities have established guidelines or regulations that will permit several types of health claims. The scientific basis for claims has been established by the US FDA and EFSA, but not yet by Codex. Evidence-based nutrition differs from evidence-based medicine, but the differences are only recently gaining recognition. Health claims on foods may provide useful information to consumers, but many will interpret the information to mean that they can rely upon the food or nutrient to eliminate a disease risk.NRVs are designed to provide a quantitative basis for comparing the nutritive values of foods, helping to illustrate how specific foods fit into the overall diet. The INL-98 and the mean of adult male and female values provide NRVs that are sufficient when used as targets for individual intakes by most adults.WTO recognizes Codex as the primary international authority on food issues. Current regulatory schemes based on recommended dietary allowances are trade restrictive. A substantial number of decisions by the EFSA could lead to violation of WTO agreements.
Keywords: Codex Alimentarius; Bioavailability; Health claims; Nutrient reference values; World Trade Organization; WTO agreements

The beneficial effect of fiber supplementation in high- or low-fat diets on fetal development and antioxidant defense capacity in the rat by Yan Lin; Xing-fa Han; Zheng-feng Fang; Lian-qiang Che; De Wu; Xiu-qun Wu; Cai-mei Wu (19-27).
There is mounting evidence that an imbalance in oxidant/antioxidant activities plays a pivotal role in fetal development.To determine the effects of maternal intake of fat and fiber on fetal intrauterine development and antioxidant defense systems of rats.Virgin female Sprague–Dawley rats were randomly assigned to 4 groups according to diet: the low-fat, low-fiber group (LL); the low-fat, high-fiber group (LH); the high-fat, low-fiber group (HL); and the high-fat, high-fiber group (HH). The diets were fed 4 weeks prior to breeding through day 17.5 of pregnancy. Dietary intakes of fiber (wheat bran and oat) and fat were quantitatively varied, while intakes of energy and essential nutrients were kept constant among the diets.Rats fed a fiber-rich diet had significantly improved fetal numbers, as well as enhanced activity of superoxide dismutase (SOD) and capacity of scavenging free radicals (p < 0.05). Meanwhile, the placental malondialdehyde and protein carbonyl levels were affected by the diet fat and fiber levels (p < 0.05). Compared with the LL group, the mRNA abundance of hypoxia-inducible factor 1α (HIF-1α) and thioredoxin-2 (Trx2) in the maternal liver and glutathione peroxidase 1 (GPx1) in the placenta and fetus were significantly downregulated in the HL group (p < 0.05). Furthermore, rats fed a fiber-rich diet had significantly upregulated mRNA expressions of Cu,Zn-SOD, Mn-SOD, and HIF-1α in the maternal liver (p < 0.05); Cu,Zn-SOD and Mn-SOD in the placenta (p < 0.05); and Cu,Zn-SOD in the fetus (p < 0.05).When energy intakes are equivalent, consumption of fiber in high- or low-fat diets benefits fetal development and growth, through improvements in maternal, placental, and fetal antioxidant defense capacities.
Keywords: Dietary fiber; Redox state; Antioxidant defense

Enzymatic protein hydrolysates of yellow pea seed have been shown to possess high anti-oxidant and anti-bacterial activities. The aim of this work was to confirm the anti-oxidant, anti-inflammatory and immunomodulating activities of an enzymatic protein hydrolysate of yellow field pea seeds.The anti-oxidant and anti-inflammatory properties of peptides from yellow field pea proteins (Pisum sativum L.) were investigated in LPS/IFN-γ-activated RAW 264.7 NO(−) macrophages. The immunomodulating potential of pea protein hydrolysate (PPH) was then studied in a murine model.Pea protein hydrolysate, after a 12 h pre-treatment, showed significant inhibition of NO production by activated macrophages up to 20%. Moreover, PPH significantly inhibited their secretion of pro-inflammatory cytokines, TNF-α- and IL-6, up to 35 and 80%, respectively. Oral administration of PPH in mice enhanced the phagocytic activity of their peritoneal macrophages and stimulated the gut mucosa immune response. The number of IgA+ cells was elevated in the small intestine lamina propria, accompanied by an increase in the number of IL-4+, IL-10+ and IFN-γ+ cells. This was correlated to up-regulation of IL-6 secretion by small intestine epithelial cells (IEC), probably responsible for B-cell terminal differentiation to IgA-secreting cells. Moreover, PPH might have increased IL-6 production in IECs via the stimulation of toll-like receptors (TLRs) family, especially TLR2 and TLR4 since either anti-TLR2 or anti-TLR4 was able to completely abolish PPH-induced IL-6 secretion.Enzymatic protein degradation confers anti-oxidant, anti-inflammatory and immunomodulating potentials to pea proteins, and the resulted peptides could be used as an alternative therapy for the prevention of inflammatory-related diseases.
Keywords: Anti-oxidant; Anti-inflammatory; Immunomodulating; Pea proteins; Cytokines

Hesperidin, a flavanone present in citrus fruits, has been identified as a potent anticancer agent because of its proapoptotic and antiproliferative characteristics in some tumor cells. However, the precise mechanisms of action are not entirely understood.The main purpose of this study is to investigate the involvement of peroxisome proliferator-activated receptor-gamma (PPARγ) in hesperidin’s anticancer actions in human pre-B NALM-6 cells, which expresses wild-type p53.The effects of hesperidin on cell-cycle distribution, proliferation, and caspase-mediated apoptosis were examined in NALM-6 cells in the presence or absence of GW9662. The expression of peroxisome proliferator-activated receptor-gamma (PPARγ), p53, phospho-IκB, Bcl-2, Bax, and XIAP proteins were focused on using the immunoblotting assay. The transcriptional activities of PPARγ and nuclear factor-kappaB (NF-κB) were analyzed by the transcription factor assay kits. The expression of PPARγ and p53 was analyzed using the RT-PCR method.Hesperidin induced the expression and transcriptional activity of PPARγ and promoted p53 accumulation and downregulated constitutive NF-κB activity in a PPARγ-dependent and PPARγ-independent manner. The growth-inhibitory effect of hesperidin was partially reduced when the cells preincubated with PPARγ antagonist prior to the exposure to hesperidin.The findings of this study clearly demonstrate that hesperidin-mediated proapoptotic and antiproliferative actions are regulated via both PPARγ-dependent and PPARγ-independent pathways in NALM-6 cells. These data provide the first evidence that hesperidin could be developed as an agent against hematopoietic malignancies.
Keywords: Hesperidin; PPAR-gamma; p53; Ikappa B; NF-kappaB

A preliminary investigation of the impact of catechol-O-methyltransferase genotype on the absorption and metabolism of green tea catechins by Rosalind J. Miller; Kim G. Jackson; Tony Dadd; Beate Nicol; Joanne L. Dick; Andrew E. Mayes; A. Louise Brown; Anne M. Minihane (47-55).
Green tea is thought to possess many beneficial effects on human health. However, the extent of green tea polyphenol biotransformation may affect its proposed therapeutic effects. Catechol-O-methyltransferase (COMT), the enzyme responsible for polyphenolic methylation, has a common polymorphism in the genetic code at position 158 reported to result in a 40% reduction in enzyme activity in in vitro studies. The current preliminary study was designed to investigate the impact of COMT genotype on green tea catechin absorption and metabolism in humans.Twenty participants (10 of each homozygous COMT genotype) were recruited, and plasma concentration profiles were produced for epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), epicatechin (EC) and 4′-O-methyl EGCG after 1.1 g of Sunphenon decaffeinated green tea extract (836 mg green tea catechins), with a meal given after 60 min.For the entire group, EGCG, EGC, EC, ECG and 4′-O-methyl EGCG reached maximum concentrations of 1.09, 0.41, 0.33, 0.16 and 0.08 μM at 81.5, 98.5, 99.0, 85.5 and 96.5 min, respectively. Bimodal curves were observed for the non-gallated green tea catechins EGC and EC as opposed to single-peaked curves for the gallated green tea catechins EGCG and ECG. No significant parametric differences between COMT genotype groups were found.In conclusion, the COMT Val(158/108)Met does not appear to have a dramatic influence on EGCG absorption and elimination. However, further pharmacokinetic research is needed to substantiate these findings.
Keywords: COMT; Flavan-3-ol; Green tea; Pharmacokinetics

Dietary d-limonene alleviates insulin resistance and oxidative stress–induced liver injury in high-fat diet and L-NAME-treated rats by Jesudoss Victor Antony Santiago; Jayaraman Jayachitra; Madhavan Shenbagam; Namasivayam Nalini (57-68).
Nonalcoholic fatty liver disease (NAFLD) is one of the most common etiologies of chronic liver disease worldwide. The pathogenesis of metabolic syndrome associated with NAFLD is still under debate.This study has investigated the hepatic biochemical and histological changes and also insulin resistance in metabolic syndrome associated with NAFLD.Young male Wistar rats fed a high-fat diet (HFD 42.2% beef tallow) together with N ω -nitro-l-arginine methyl ester (L-NAME; 80 mg/L in drinking water) for 8 weeks and subsequently with 2% d-limonene for the final 4 weeks.HFD-fed rats treated with L-NAME showed increased systolic blood pressure, heart rate, fasting blood glucose, plasma insulin, hepatic marker enzymes, hepatic lipids, circulatory lipid peroxidation by-products, and hepatic phase I enzyme activities with decreased circulatory nonenzymic antioxidant concentrations and hepatic phase II enzyme activities. Dietary supplementation with d-limonene reversed the HFD and L-NAME-induced changes and restored pathological alteration of liver and pancreas.These data provide new insights into the therapeutic approach of d-limonene against the development of the metabolic syndrome associated with NAFLD.
Keywords: Nonalcoholic fatty liver disease; Metabolic syndrome; High-fat diet; L-NAME; d-limonene

Acute antioxidant supplementation may modulate oxidative stress and some immune perturbations that typically occur following prolonged exercise. The aims of the present study were to examine the effects of acutely consuming dark chocolate (high polyphenol content) on plasma antioxidant capacity, markers of oxidative stress and immunoendocrine responses to prolonged exercise.Fourteen healthy men cycled for 2.5 h at ~60% maximal oxygen uptake 2 h after consuming 100 g dark chocolate (DC), an isomacronutrient control bar (CC) or neither (BL) in a randomised-counterbalanced design.DC enhanced pre-exercise antioxidant status (P = 0.003) and reduced by trend (P = 0.088) 1 h post-exercise plasma free [F2-isoprostane] compared with CC (also, [F2-isoprostane] increased post-exercise in CC and BL but not DC trials). Plasma insulin concentration was significantly higher pre-exercise (P = 0.012) and 1 h post-exercise (P = 0.026) in the DC compared with the CC trial. There was a better maintenance of plasma glucose concentration on the DC trial (2-way ANOVA trial × time interaction P = 0.001), which decreased post-exercise in all trials but was significantly higher 1 h post-exercise (P = 0.039) in the DC trial. There were no between trial differences in the temporal responses (trial × time interactions all P > 0.05) of hypothalamic–pituitary–adrenal axis stress hormones, plasma interleukin-6, the magnitude of leukocytosis and neutrophilia and changes in neutrophil function.Acute DC consumption may affect insulin, glucose, antioxidant status and oxidative stress responses, but has minimal effects on immunoendocrine responses, to prolonged exercise.
Keywords: Polyphenols; Dark chocolate; Exercise; Neutrophil; Oxidative stress; Innate immune system

Evaluation of anthropometric indices for metabolic syndrome in Chinese adults aged 40 years and over by Yan-Hong He; Ying-Chun Chen; Guo-Xin Jiang; Hong-Er Huang; Rui Li; Xiao-Ying Li; Guang Ning; Qi Cheng (81-87).
The prevalence of metabolic syndrome (MetS) is increasing worldwide with a marked impact in cardiovascular disease (CVD) and diabetes risk.To evaluate the anthropometric indices for metabolic syndrome (MetS) and determine the optimal cut-off values of waist circumference (WC), body mass index (BMI), and waist height ratio (WHtR) for MetS in Chinese adults aged 40 years and over.A sample of Chinese adults aged 40 years and over including 430 men and 638 women was investigated. Blood pressure, weight, height, and WC were measured; HDL-cholesterol (HDL-C), Triglyceride (TG), and plasma glucose were examined. Receiver operating characteristics (ROC) curve analyses were used to evaluate the optimal cut-off point of WC, BMI, and WHtR for MetS.According to the ROC curve analysis, the optimal cut-off point for WC was found to be 84.0 cm in men and 80.0 cm in women; for BMI, it was 26.0 in men and 25.0 in women; and for WHtR, it was 0.5 in both men and women. WHtR has the highest predictive value for fast plasma glucose in women, while BMI has the better prediction of dyslipidemia in men.Anthropometric indices (WC, BMI, and WHtR) are useful screening tools for obesity, MetS, and CVD risk factors. BMI may be a better indicator than the others for screening obesity, dyslipidemia, and other risk components in Chinese men aged 40 years and over, while WHtR may be better for Chinese women, especially among those aged 70 years and over.
Keywords: Waist circumference; Body mass index; Waist height ratio; Receiver operating characteristics

Diets rich in saturated fat and/or salt differentially modulate atrial natriuretic peptide and renin expression in C57BL/6 mice by Milton Vieira Costa; Caroline Fernandes-Santos; Tatiane da Silva Faria; Marcia Barbosa Aguila; Carlos Alberto Mandarim-de-Lacerda (89-96).
To study the effects of a diet rich in salt and/or saturated fat on atrial natriuretic peptide (ANP)-granules, hypertension, renin expression, and cardiac structure in C57Bl/6 mice.Young adult male mice were separated into four groups (n = 12) and fed one of the following for 9 weeks: standard chow/normal salt (SC-NS), high-fat chow/normal salt (HF-NS), standard chow/high salt (SC-HS) and high-fat chow/high salt (HF-HS). Alterations in the serum ANP, ultrastructural analysis of cardiomyocytes that produce ANP, structural analysis of the left ventricle, blood pressure, renin expression, glomerular filtration rate (GFR), feed efficiency, and lipid and glucose parameters were examined.The HF-NS diet showed a small increase in ANP production and left ventricular hypertrophy, increased food efficiency, and abnormal lipid and glucose parameters. The SC-HS diet showed a large increase in ANP granules in myocytes and corresponding elevation in ANP serum levels, left ventricular hypertrophy, hypertension, decrease in renin levels, and increase in GFR. The combination of the two diets (HF-HS) had an additive effect.The incorporation of a high-fat high-salt diet induced ultrastructural changes in cardiomyocytes, increased the production of ANP and increased its serum level, and reduced the amount of renin in the kidney.
Keywords: Atrial natriuretic peptide; Hypertension; High-fat high-salt diet; Stereology; Rennin

Implication of Vitamin A deficiency on vascular injury related to inflammation and oxidative stress. Effects on the ultrastructure of rat aorta by Laura V. Gatica; Liliana B. Oliveros; Matías F. Pérez Díaz; Nora S. Domínguez; Miguel W. Fornes; María S. Gimenez (97-106).
Vitamin A deficiency induces activation of NF-kB and impairs activities of antioxidant enzymes in aorta.We study the effect of vitamin A deficiency on the aorta histoarchitecture and the possibly contribution of its prooxidant and inflammatory effects to artery alterations.Twenty-one-day-old Wistar male rats were fed during 3 months with vitamin A-deficient diet (−A, n = 8) or the same diet containing 8 mg of retinol palmitate/kg of diet (+A, control, n = 8). In aortas, thiobarbituric reactive substances and reduced glutathione levels were measured by spectrophotometry. Expressions of TNF-alpha, NOX-2, VCAM-1, and TGF-beta1 were assessed by RT–PCR and Western Blot. The morphology of aorta was examined by light and transmission electron microscopy.In −A rats, high levels of TBARS in serum and aorta and low levels of GSH in aorta were found. An increased expression of TNF-alpha, NOX-2, VCAM-1, and TGF-beta1 in aorta from −A rats was observed. Examination of the intimal layer by light microscopy indicated the presence of an irregular surface in −A aortas. TEM studies showed large vacuoles and multivesicular bodies along the endothelium and also multivesicular bodies in the subendothelial space of aortas from −A rats. Furthermore, the histological appearance of internal elastic lamina was different from control. Small vesicles in the medial layer were observed in aortas from vitamin A-deficient rats.Vitamin A deficiency produces histoarchitectural alterations in aorta, which can be associated, at least in part, to the oxidative stress and inflammation induced by vitamin A deficiency.
Keywords: Vitamin A; Aorta histoarchitecture; TNF-alpha; NOX-2; VCAM-1; TGF-beta1

Modified apple polysaccharide prevents against tumorigenesis in a mouse model of colitis-associated colon cancer: role of galectin-3 and apoptosis in cancer prevention by Yuhua Li; Li Liu; Yinbo Niu; Juan Feng; Yang Sun; Xianghe Kong; Yongchun Chen; Xiaoyan Chen; Hongquan Gan; Shousong Cao; Qibing Mei (107-117).
Colorectal cancer (CRC) is one of the most common and preventable cancers. Regular consumption of apples is conducive to reduction in CRC risk.To evaluate effects of modified apple polysaccharide (MAP) on tumorigenesis in a mouse model of colitis-associated colon cancer.One hundred male ICR mice were administered with 1, 2-dimethyl-hydrazine (DMH) and dextran sodium sulfate (DSS). Forty mice were given no further treatment, the rest were fed basal diet blended with three different doses of MAP; 2.5, 5, and 10% (20 mice in each group).MAP significantly protected ICR mice against DMH/DSS-induced tumorigenesis. The incidence of tumor development was 90% (18/20) in the mice treated with DMH/DSS, but that was reduced to 25% (5/20), 15% (3/20), and 5% (1/20), respectively, in the mice treated with basal diets plus 2.5, 5, and 10% of MAP. Study of apoptosis of colonic epithelial cells revealed that MAP moderately increased apoptosis, suggesting that the anti-tumor potency of MAP was probably attributed to its ability to induce apoptosis. Western blot analysis demonstrated that carbohydrate-binding protein galectin-3 changed in both the nucleus and the cytoplasm during the process from colitis to colon cancer in the model. And MAP could inhibit the binding of galectin-3 to its ligand: this is, at least in part, the possible mechanism of MAP by enhancing apoptosis and preventing tumorigenesis.These data suggest that MAP has a potential role in clinical prevention and treatment for colon cancer.
Keywords: Modified apple polysaccharide; Galectin-3; Apoptosis; Colitis-associated colon cancer; Cancer prevention

The amino acid sensor GCN2 biases macronutrient selection during aging by Anne-Catherine Maurin; Cédric Chaveroux; Sarah Lambert-Langlais; Valérie Carraro; Céline Jousse; Alain Bruhat; Julien Averous; Laurent Parry; David Ron; Josette Alliot; Pierre Fafournoux (119-126).
Selection of a balanced diet has a determinant impact on human health. Individual food preferences involve socio-cultural as well as physiological factors and evolve during aging. In mammals, physiological mechanisms governing food choices appear to require the sensing of nutrient concentrations in diet. This is particularly the case for dietary amino acids that are sensed by the protein kinase GCN2. It has been reported that GCN2 is involved in the adaptive response to amino acid imbalanced diets at the level of food intake and lipid metabolism. Here, we hypothesized that GCN2 may play a role in macronutrient selection and its age-related changes.Two groups of wild-type and GCN2 knock-out mice were subjected to a food self-selection protocol at ages 6, 12, 18 and 24 months. During each test, mice were allowed to create their own diets by selecting between three separate food sources, each containing either protein, fat or carbohydrates.Our results show that the absence of GCN2 had two main age-related effects. First, it exacerbated fat preference at the expense of carbohydrate consumption. Second, it prevented the increase in protein intake.These findings indicate that, in omnivores, the GCN2 ancient pathway participates in the control of food preference.
Keywords: Diet selection; Aging; GCN2; Macronutrient; Ingestive behavior