http://informahealthcare.com/ijf ISSN: 0963-7486 (print), 1465-3478 (electronic) Int J Food Sci Nutr, 2014; 65(5): 637–645 ! 2014 Informa UK Ltd. DOI: 10.3109/09637486.2014.893283

STUDIES IN HUMANS

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Effects of consumption of whole grain foods rich in lignans in healthy postmenopausal women with moderate serum cholesterol: a pilot study A. Durazzo1, M. Carcea1, H. Adlercreutz2, E. Azzini1, A. Polito1, L. Olivieri3, M. Zaccaria1, C. Meneghini1, F. Maiani1, G. Bausano3, F. Martiri1, A. Samaletdin2, A. Fumagalli1, A. Raguzzini1, E. Venneria1, M. S. Foddai1, D. Ciarapica1, B. Mauro1, F. Volpe3, and G. Maiani1 1

Agricultural Research Council-Food and Nutrition Research Centre (CRA-NUT), Rome, Italy, 2Institute for Preventive Medicine, Nutrition and Cancer, Folkha¨lsan Research Center, Division of Clinical Chemistry, University of Helsinki, Finland, and 3ASL Roma B, Nutrition and Preventive Medicine Unit, Rome, Italy Abstract

Keywords

This study aims at investigating the effect of an experimental period of intake of whole grain foods rich in lignans as part of an habitual diet on the plasma and urinary excretion of enterolignans, the biomarkers of lipid metabolism and the immunological and antioxidant status in a group of postmenopausal women with moderate serum cholesterol. A randomized double-blind crossover study was completed on 13 subjects in 12-weeks after protocol approval of an ethical committee. The subjects consumed whole grain foods high in lignans (30 g/d of breakfast cereals or biscuits, etc., 80 g/d of whole grain pasta) or refined grain foods for 4 weeks, separated by a 2-weeks wash-out period. A modest hypocholesterolemic effect (p50.05) of the whole grain diet was observed and the intake of whole grain products rich in lignans was also associated with an increase in urinary enterodiol excretion (p50.05).

Enterolignans, lignans, randomized double-blind crossover study, whole grain foods

Introduction By the late twentieth century, the importance of whole grains had been rediscovered, first by the natural foods movements and later by the scientific community. In recent years, there has been an evaluation of the role of whole grain cereals in the diet and their possible implication in the prevention of chronic diseases. In particular, from several investigations it appears that whole grain cereal foods could reduce the risk of diseases such as coronary heart diseases, stroke, cancer and diabetes (Giacco et al., 2009; Harris & Kris-Etherton, 2010; Jacobs & Gallaher, 2004; Jensen et al., 2004; Tighe et al., 2010; Venn & Mann, 2004; Ye et al., 2012). The beneficial properties of whole cereal grains are attributed in part to their unique phytochemical composition made by vitamins and minerals, unsaturated fatty acids, tocotrienols, tocopherols, insoluble and soluble fiber, phytosterols, stanols, sphingolipids, phenolic acids, phytates, lignans, etc (Jonnalagadda et al., 2011; Slavin, 2004). Several studies have suggested that, within the group of cereal phytochemicals, the presence of lignans could be one of the factors that might explain the reduced incidence of chronic diseases such as cardiovascular diseases, cancer and diabetes in people consuming a diet rich in whole grain products (Adlercreutz, 2007; Adlercreutz & Mazur, 1997).

Correspondence: A. Durazzo, Agricultural Research Council-Food and Nutrition Research Centre (CRA-NUT), Rome, Italy. Tel: +390651494651. Fax: +390651494550. E-mail: alessandra.durazzo@ entecra.it

History Received 11 October 2013 Revised 30 January 2014 Accepted 7 February 2014 Published online 10 March 2014

Lignans are attributable to a wide range of physiological functions and beneficial properties (Miur, 2010). They have in fact been implicated as having antitumorigenic (Saarinen et al., 2007; Thompson et al., 1996), anticarcinogenic (Bergman Jungestrom et al., 2011; Velentzis et al., 2009), estrogenic and/ or anti-estrogenic (Collins et al., 1997), and antioxidant (Kitts et al., 1999; Prasad, 2000) properties. Lignans are a class of secondary plant metabolites, that belong to the group of diphenolic compounds derived from the combination of two phenylpropanoid C6–C3 units at the b and b0 carbon atoms. They have a chemical structure like the 1,4-diarylbutan. The range of their structures and biological activities is broad. They are derived from the shikimic acid biosynthetic pathway. Plant lignans occur as glycosides possibly in various forms widely distributed in several plant species (Durazzo et al., 2013a; Milder et al., 2005; Penalvo et al., 2008; Smeds et al., 2009; Thompson et al., 2006). The main sources of dietary lignans are oilseeds (e.g. flax, soy, rapeseed and sesame), whole grain cereals (e.g. wheat, oats, rye, barley), legumes and various vegetables and fruit (particularly berries). The most concentrated sources of lignans amongst edible parts of plants are flaxseed and sesame seed (Thompson et al., 1997). In cereal grains they are mostly concentrated in the outer layers (Adlercreutz & Mazur, 1997; Esposito et al., 2005; Smeds et al., 2007). Several investigations have shown that, once in the human colon, a major fraction of dietary lignans are converted to enterolignans, enterolactone and enterodiol by the intestinal microflora before reaching the circulation: enterolignans have a similar structure to the human hormone estrogen and so may have estrogenic/anti-estrogenic effects

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(Heinonen et al., 2001; Rowland et al., 2000; Setchell & Adlercreutz, 1988; Wang et al., 2000) Consumption of lignan-rich diets, which contain vegetables, fruits and whole grain products, may protect against chronic diseases (Adlercreutz, 2007; Dodin et al., 2008; Lemay et al., 2002; Peterson et al., 2010; Webb & McCullough, 2005). Jacobs et al. (2000) showed that in post-menopausal women, the risk of mortality was inversely associated with their whole grains consumption but not with their refined grains one, whereas Buck et al. (2011) showed that postmenopausal patients with breast cancer who have high serum enterolactone levels have better survival rates. This study aimed at investigating the effect of an experimental period of intake of whole grain cereal-based foods high in lignans as part of an habitual diet on the plasma and urinary excretion of enterolignans, on the plasma biomarkers of lipid metabolism and on the plasma immunological and antioxidant status of a group of postmenopausal women with moderate serum cholesterol.

Materials and methods

Subjects The study was conducted in accordance with the Declaration of Helsinki on human trial performance, and informed consent was provided by all participants. They were informed about the research purpose and procedure, benefits and risks, having the freedom to drop out from the study at any time. The study protocol was approved by the Ethics Committee of ASL Roma B. Healthy postmenopausal women were recruited by the ASL Roma B, Nutrition and Preventive Medicine Unit. Forty-six were enrolled, and, after screening, 20 were participated. Inclusion criteria were as follows: amenorrhea for more than one year and no more than 5 years, age 48–58 years, absence of acute or chronic diseases or metabolic disorders, smoking habits (510 g tobacco/d), alcohol consumption (520 g/d), no drugs (aspirin, anti-inflammatory medications, antibiotics) for the 2 weeks before the experiments, no use of vitamin or mineral supplements for the 4 weeks before the experiments, no use of laxatives, lipid lowering drugs and no dietary fiber supplementation or other substance able to affect the bowel function, no hormone replacement therapy and/or chemotherapy. Seven subjects withdrew from the study before completion.

Test food Foods usually consumed at breakfast in Italy (breakfast cereals, rusks, biscuits, puffed grains) used in the whole grain cereal based food period were commercial products bought at supermarkets and chosen on the basis of their high lignans content, whereas multi-grain pasta was purchased directly from one of the major Italian pasta manufacturer. Samples from a great number of commercial products available on the Italian market were preliminary studied for their lignan content by the method of Durazzo et al. (2013b). The method adopts alkaline hydrolysis as the step prior to enzymatic hydrolysis. Under alkaline conditions, ester-linked oligomers of lignan are hydrolyzed to give the lignan monomer. Quantitative analyses were performed using ESA series HPLC, equipped with an eight-channel coulometric electrode array detector and an ESA coularray operating software that control the equipment and perform data processing (ESA, Chelmsford, MA). Isolariciresinol, lariciresinol, secoisolariciresinol, pinoresinol and matairesinol were detected and quantified. The sum of identifiable lignans was indicated as total lignans. Contents of lignans in the selected foods which were subsequently offered for consumption in this study are reported in Table 1.

Study design and diet The study was a double-blind, randomized, crossover intervention trial. Volunteers followed a pre-treatment period consisting of 2 weeks of habitual diet without consuming lignans-rich foods. The subjects then consumed whole grain foods high in lignans (30 g/d breakfast cereals or biscuits, etc., 80 g/d whole grain pasta) or refined grain foods for 4 weeks, separated by a 2-weeks wash-out period. Both the free diet and the pre-treatment periods were used to eliminate carryover effects, i.e. residual effects of the preceding treatment on the tested variables. All subjects were initially interviewed by a doctor who explained the study: anthropometric measurements (height, body weight, waist circumference) were performed in the morning in a fasting condition by the same skilled observer according to a standardized procedure (Lohman et al., 1988) and the blood pressure was measured in a quiet room after the subjects had been resting for 10 min. Anthropometric characteristics and blood pressure were measured at weeks 0, 2 and 4 of each treatment. The subjects consumed whole grain or refined cereal-based foods as a part of their habitual diet and were advised to avoid any dietary changes during the study and to follow a dietary

Table 1. Total lignans content (Mean ± SE) in whole grain test products included in the habitual daily diet during the whole grain based food treatment.

Products Breakfast cereals (brand 1) Breakfast cereals (brand 2) Breakfast cereals (brand 3) Whole grain biscuits Compressed puffed rice Puffed barley Whole grain rusks (brand 1) Whole grain rusks (brand 2) Whole grain rusks (brand 3) Multigrain pasta

Composition Cereals 48.4% (whole oat flour 35.8%; maize flour), wheat germ. Whole cereals (54%) (flour of whole oat, whole rice, whole wheat), cereal agglomerate (19%), oat bran, barley malt. Cornflakes and bran (31.5%), toasted oatmeal (30%), rice aggregate and bran (25%), sugar-coated barley flakes (9%), almonds (4.5%). Wheat flour (51%), barley flakes (3%), rye flakes (1.8%), rice flour (1.7%), oatmeal (1.3%), maize flour (1.2%), wheat malt. White rice and dehulled rice Whole barley. Wheat flour, cereals (rice, barley, wheat, oats, rye) 9.2%, yeast, non hydrogenated vegetable fat, sugar, oatmeal 2.1%, barley and corn malt, salt, malted wheat flour. Wheat flour, sugar, yeast, non hydrogenated vegetable fat, barley and corn malt (2.6%), skimmed milk powder, butter, salt, toasted barley malt (0.6%), malted wheat flour, spices. Wheat flour type ‘‘0’’, sugar, cereals 12% (oats, barley, spelt), non hydrogenated vegetable oil, glucose-fructose syrup, whole milk powder, yeast, cocoa fiber, salt. Dry pasta with different grains (cereals, legumes and flaxseed).

Total lignans (mg/100 g wet basis) 148.6 ± 3.7 237.5 ± 7.0 265.6 ± 8.4 73.5 ± 3.0 113.6 ± 5.9 198.3 ± 16.3 283.2 ± 10.8 112.1 ± 2.7 143.5 ± 0.5 8759.0 ± 72.8

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DOI: 10.3109/09637486.2014.893283

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exclusion list. Moreover, they were asked to maintain their lifestyle, including work schedules and usual patterns of physical activity. Subjects were periodically provided with the test whole grain cereal foods and the compliance with the controlled diets was kept by asking subjects to record the test cereal food portions eaten daily. Food intake data were collected at the beginning and at the end of the supplementation by dietitians or trained personnel using the 4-day recall-record method (2 week and 2 weekend days) fully described by Polito et al. (2005). The daily test cereal foods portions were identified according to both the standard food patterns and portions specific for the Italian population (DietoMetro, 1999). A trained dietician checked the records in the presence of the subject in order to avoid the bias related to incomplete and/or inconsistent reporting. Food intake data were transformed into nutrient intake using the Italian food composition tables (INRAN, 2000). Laboratory measurements Chemicals All solvents were of HPLC or Optima grade and purchased from Carlo Erba (Milan, Italy). Common reagents and standards were purchased from Sigma–Aldrich Srl (Milan, Italy), Extrasynthese (Genay, France), Chemical Research (Rome, Italy), Sentinel Diagnostics (Italy), Fluka (Buchs, Switzerland), Cayman Chemical Company (Ann Arbor, MI), Diaclone (Besanc¸on, France), Randox Laboratories Ltd (London, UK) and were of the highest available grade. Double-distilled water (Millipore, Milan, Italy) was used throughout the study. Blood collection and analyses Blood samples were taken at the beginning, after 15 days and at the end of each intervention period. Blood from overnight fasting was collected by venipuncture into tubes containing anticoagulant (heparin or EDTA) and was protected from light exposure. The plasma was immediately separated by centrifugation and aliquots were stored at 80  C until analysis. Precision and reproducibility of measurements were monitored using pooled human plasma or a multi-parameter control for quantitative clinical chemistry determinations (Clin Chem Control 1; Sentinel Diagnostics, Milan, Italy). Glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride concentrations were measured using enzymatic tests (Sentinel Diagnostics, Milan, Italy). Plasma total antioxidant capacity was measured by ferric reducing ability of plasma (FRAP) (Benzie & Strain, 1996). The FRAP assay is based on the reduction of the Fe3+–TPTZ complex to the ferrous form at low pH monitored at 595 nm by a Sunrise absorbance plate reader (Tecan Italia Srl, Segrate, Italy). FRAP values were obtained by comparing the absorption changes in the test mixture with those obtained from increasing concentrations of Fe2+. Plasma nitric oxide concentrations were evaluated spectrophotometrically using commercial kits supplied by Cayman Chemical Company, Ann Arbor, MI. An enzyme-linked immunosorbent assay was used for the measurement of plasma pro-inflammatory cytokines such a interleukin 1b (IL-1b), interleukin (IL-6), tumor necrosis factor a (TNF-a), according to the manufacturer’s instructions (Diaclone, Besanc¸on, France). An high-performance liquid chromatography coupled with coulometric electrode array detection (HPLC-CEAD) was used to quantify enterolignans, enterolactone (Enl) and enterodiol

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(End) in plasma (Penalvo et al., 2004) and urine (Nurmi et al., 2003) following published methods. Red blood cells hemolysis was induced by NaCl buffer. The percentage of hemolysis was determined spectrophotometrically at 540 nm (Randox Laboratories Ltd, London, UK). Glutathione peroxidase (GPx) (which provides a rapid and easily automated mean of assessment of the antioxidant defences possessed by an individual) was determined spectrophotometrically using commercial kits supplied by Randox Laboratories Ltd, London, UK. Activity of superoxide dismutase (SOD) was evaluated spectrophotometrically using commercial kits supplied by Cayman Chemical Company, Ann Arbor, MI. 24-h urine collection and analysis 24-h urine samples were taken at the beginning and at the end of each intervention period. Each 24-h urine was collected separately into bottles containing 1 g of ascorbic acid. Isolariciresinol, lariciresinol, secoisolariciresinol, pinoresinol and matairesinol were quantified in urine samples by high-performance liquid chromatography with coulometric electrode array detection following published method (Nurmi et al., 2003). Statistical analysis Data are expressed as means ± SE (Standard Error). The Student t-test was applied for testing differences between two treatments. Differences among treatments were tested by the two-way analysis of variance (ANOVA) followed by Tukey’s HSD multiple rank test or by Paired T test. The limit of statistical significance was set at p50.05. The computer program used was Statistica for Windows (release 4.5; StatSoft Inc, Vigonza PD, Italy).

Results and discussion Anthropometric characteristics and menopausal status, recorded during the screening visits, are reported in Table 2. The effects of consumption of whole grain cereal based foods rich in lignans on different physiological parameters of healthy postmenopausal women are shown in Tables 3–8 and Figure 1. Dietary intake No significant differences in total energy intake between baseline and after treatment in both interventions group were observed (Table 3). Significant decrease in protein (p50.04) and increase in carbohydrate (p50.05) with respect to baseline were observed after whole grain cereal-based foods, whereas a decrease of total fiber (p50.05) was observed after consumption of refined cerealbased foods. Table 2. Baseline parameters of women. Parameters Anthropometric characteristics Age (years) Weight (kg) Height (cm) Body Max Index (BMI) (kg/m2) Waist circumference (cm) Menopausal status Sonatotropin hormone (STH) (ng/mL) Follicle-stimulating hormone (FSH) (mIU/mL) Luteinizing hormone (LH) (mIU/mL) 17-b-estradiol (pg/mL) 17-a-hydroxyprogesterone (ng/mL) Thyroglobulin (ng/mL)

Mean ± SE 52.8 ± 1.0 64.2 ± 2.8 157.1 ± 2.2 26.4 ± 0.1 80.9 ± 2.1 2.9 ± 0.7 128.0 ± 13.9 39.0 ± 2.8 35.0 ± 14.1 0.8 ± 0.1 5.7 ± 1.5

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Table 3. Dietary intake of macronutrient and lignans in whole grain and refined cereal based foods consumption groups at baseline and after treatmenty.

Whole grain Energy (kcal/d) Protein (g/d) (% energy) Fat (g/d) (% energy) Carbohydrates (g/d) (% energy) Fiber (g/d) Alcohol (g/d) Lignans (mg/d) Refined grain Energy (kcal/d) Protein (g/d) (% energy) Fat (g/d) (% energy) Carbohydrates (g/d) (% energy) Fiber (g/d) Alcohol (g/d) Lignans (mg/d)

Baseline

4 weeks

p Valuez

1568 ± 285 63.5 ± 13.8 16.4 ± 3.5 65.4 ± 15.3 37.4 ± 8.8 178 ± 41.5 42.7 ± 9.9 15.2 ± 5.3 8.3 ± 7.9 653 ± 262

1655 ± 287 61.1 ± 14.5 14.8 ± 3.6 71.2 ± 14.3 38.8 ± 7.8 189.7 ± 46.7 42.8 ± 10.6 15.4 ± 4.8 8.2 ± 10.2 6961 ± 1370

n.s. n.s. 0.04 n.s. n.s. 0.05 n.s. n.s. n.s. 0.001

1572 ± 286 62.9 ± 11.9 16.3 ± 3.4 66.7 ± 14.7 38.1 ± 4.7 179.5 ± 40.6 42.9 ± 6.7 15.1 ± 4.9 7.8 ± 7.2 655 ± 260

1676 ± 353 64.5 ± 10.5 15.7 ± 3.7 75.4 ± 17.1 40.5 ± 9.1 184.9 ± 55.4 41.1 ± 12.4 13.1 ± 3.5 6.6 ± 10.6 659 ± 284

n.s. n.s. n.s. n.s. n.s. n.s. n.s. 0.05 n.s. n.s.

yMean ± SE. zPaired T test. Table 4. Effect of whole grain versus refined cereal based foods consumption on weight, BMI, systolic and diastolic blood pressurey. Intervention period

0

2 weeks

4 weeks

Weight (kg) b

63.7 ± 2.7a 64.5 ± 1.8 n.s. BMI (kg/m2)

63.3 ± 2.5a 64.3 ± 2.7 n.s.

Whole grain Refined grain p Valuez

64.0 ± 2.7 64.3 ± 1.9 n.s.

Whole grain Refined grain p Valuez

25.7 ± 1.2a 25.6 ± 1.2a 25.9 ± 1.2b 26.1 ± 1.2 25.8 ± 1.0 26.1 ± 1.2 n.s. n.s. n.s. Systolic blood pressure (mmHg)

Whole grain Refined grain p Valuez

118 ± 3.1 120 ± 2.51 116 ± 2.2 118 ± 3.1 119 ± 2.51 115 ± 1.9 n.s. n.s. n.s. Diastolic blood pressure (mmHg)

Whole grain Refined grain p Valuez

75 ± 2.2 75 ± 2.5 n.s.

76 ± 1.9 76 ± 1.4 n.s.

74 ± 1.4 75 ± 1.9 n.s.

yMean ± SE. Repeated measures ANOVA; means along each treatment followed by different letters are significantly different (p50.001). zStudent’s t-test.

An increase (p50.001) of dietary lignans intake after whole grain cereal-based foods was observed with respect to baseline (Table 3). Body weight and blood pressure Body weight, body mass index (BMI), systolic and diastolic blood pressure are reported in Table 4. No changes in systolic and diastolic blood pressure were noted following the intervention study, while a decrease of body weight (p50.001) and BMI (p50.001) was reported. It is well known that the reduction of body weight and BMI are primarily due to changes of lifestyle,

including food and physical activity. In our sample, no differences were found in dietary habits: energy intake appears to be moderately higher after treatment (approximately 6%). Regarding physical activity each subjects completed a lifestyle questionnaire including questions of sport activities and activities during work and free time: after treatments no change in lifestyle was observed (data not shown). Even if lifestyle represents the principal factor that affects the body weight, our results does not underline this correlation. Moreover, as reported by other researches (Kilkkinen et al., 2001; Morisset et al., 2009), it is possible to assume that the observed decrease in body weight could be due to an increase of plasma enterolactone. Further studies are needed to explain this mechanism. Lipid status Results on the lipid status showed no significant difference for triglycerides and HDL-cholesterol between the two interventions and within each intervention period (data no shown), whereas a modest hypocholesterolaemic effect (p50.05) of the whole grain products was observed (Figure 1). The cholesterol-lowering effect is well documented in intervention studies with supplementation of whole meal products; this effect could be correlated to the soluble fiber content (Anderson et al., 1992; Brown et al., 1999; Leinonen et al., 2000; Zhang et al., 1992) or bioactive substances action (Jacobs et al., 2000) such as alkylresercinol (Soderholm et al., 2012a,b) and lignans (Fukumitsu et al., 2010; Lucas et al., 2007; Marblestone, 2008; Patade et al., 2008; Zhang et al., 2008). However, Hallund et al. (2006a), during a randomized, double-blind, placebo-controlled, crossover study in healthy postmenopausal women, showed that the lignan complex isolated from flaxseed does not affect plasma lipid concentrations. The meta-analysis of Pan et al. (2009) reported that flaxseed significantly reduced circulating total and LDL-cholesterol concentrations and that the hypocholesterolemic effect depended on the type of intervention, sex, phase of the menstrual cycle (Adlercreutz & Tallqvist, 1959) and initial lipid profiles of the subjects; in particular, this effect was more evident in studies that used whole products, that enrolled women (particularly postmenopausal women) and in subjects with high initial cholesterol concentrations. Glucose In our investigation, between- and within the-treatment comparison revealed no significant difference for blood glucose levels (data not shown). Literature data about the effect of lignans on glucose metabolism are few. Lemay et al. (2002) found that flaxseed supplements decreased glucose and insulin levels in 25 hypercholesterolemic postmenopausal women. Pan et al. (2007) showed that daily lignan supplementation resulted in modest, yet statistically significant improvements in glycemic control in type 2 diabetic patients without apparently affecting fasting glucose, lipid profiles and insulin sensitivity. Zhang et al. (2008) showed that in a 8-week, randomized, double-blind study, dietary flaxseed lignan extract lowered plasma cholesterol and glucose concentrations in hypercholesterolemic subjects. Penalvo & Lopez-Romero (2012) showed that urinary enterolignan concentrations are associated with lower serum TG concentrations and greater HDL cholesterol concentrations in US adults. Antioxidant parameters Table 5 reports the effects of whole grain versus refined cerealbased foods consumption on antioxidant parameters. At 4 weeks,

DOI: 10.3109/09637486.2014.893283

Effects of consumption of whole grain foods rich lignans in healthy postmenopausal women

Table 5. Effect of whole grain versus refined cereal based foods consumption on FRAP, SOD, GPXy.

Table 6. Effect of whole grain versus refined cereal based foods consumption on IL-6, IL-1b, TNF-a and NOy.

Intervention period

Intervention period

0

2 weeks

4 weeks

0

FRAP (mmol/L)

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2 weeks

4 weeks

IL-6 (pg/mL)

Whole grain Refined grain p Valuez

840.9 ± 27.6 858.2 ± 26.1 n.s.

830.7 ± 9.4 862.7 ± 11.5 p50.05 SOD (U/g Hb)

835.8 ± 14.6 807.1 ± 14.2 n.s.

Whole grain Refined grain p Valuez

2.1 ± 0.3 1.5 ± 0.2 n.s.

1.9 ± 0.2 1.9 ± 0.2 n.s. Il-1b (pg/mL)

1.8 ± 0.2 1.8 ± 0.2 n.s.

Whole grain Refined grain p Valuez

6.4 ± 0.4 4.8 ± 0.3a p50.01

6.5 ± 0.5 5.5 ± 0.4 n.s. GPX (U/g Hb)

6.4 ± 0.5 6.7 ± 0.4b n.s.

Whole grain Refined grain p Valuez

1.3 ± 0.2 1.2 ± 0.3 n.s.

1.2 ± 0.1 1.2 ± 0.2 n.s. TNF-a (pg/mL)

1.1 ± 0.1 1.2 ± 0.1 n.s.

Whole grain Refined grain p Valuez

2.3 ± 0.4 2.3 ± 0.4 n.s.

1.8 ± 0.2 1.9 ± 0.2 n.s. NO (mmol/L)

2.1 ± 0.3 1.8 ± 0.3 n.s.

Whole grain Refined grain p Valuez

43.8 ± 3.7 49.0 ± 5.4 n.s.

37.1 ± 3.4 50.9 ± 4.8 p50.05

48.7 ± 4.9 44.2 ± 4.8 n.s.

Whole grain Refined grain p Valuez

56.2 ± 4.4 52.6 ± 4.2 n.s.

59.7 ± 4.8 57.7 ± 3.6 n.s.

58.8 ± 4.5 53.2 ± 3.9 n.s.

yMean ± SE. Repeated measures ANOVA; means along each treatment followed by different letters are significantly different (p50.001). zStudent’s t-test.

FRAP, SOD, GPX did not differ between the two intervention periods (Table 5). Different studies in the literature have described and evaluated the in vitro antioxidant activity of lignans (Kitts et al., 1999; Niemeyer & Metzler, 2003; Prasad, 1997, 2000) and in animal models (MacDonald-Wicks & Garg, 2002; Pattanaik & Prasad, 1998; Prasad, 1999), although the mechanism of action is unclear. The antioxidant capacity attributed to lignans does not result in a significant decrease of the oxidative stress in in vivo studies by Hallund et al. (2006a) and Coulman et al. (2009). Woodside et al. (2006) studied, in a short-term (1 week) phytoestrogen supplementation, the effect of a phytoestrogen-rich (80 mg total phytoestrogens) supplement containing soy, rye and linseed and showed that there was no effect of supplementation on lipids or markers of antioxidant status. Coulman et al. (2009) in a randomized crossover study, in which 16 postmenopausal women supplemented their diets with food bars containing either 25 g of unground flaxseed, or sesame seeds, or their combination found a minimal antioxidant and lipidlowering effect. Inflammation and endothelial markers In Table 6, IL-6, IL-1b, TNF-a (pg/mL ± ds) and nitric oxide (mmol/L ± ds) in plasma are reported. No significant differences in IL-6, IL-1b, TNF-a were found between the two treatments and along each treatment. It is reasonable to assume that the whole grain cereal-based foods may affect other systemic or local inflammatory pathways not examined in this study. Hallund et al. (2008) studied the effect of a lignan complex isolated from flaxseed on inflammation markers in healthy postmenopausal women: no significant differences in IL-6, TNF-a, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1 and monocyte chemo attractant protein-1 were found between the lignan complex intervention period and the placebo period. Wu et al. (2009) investigated the effects of sesame supplementation in humans on blood lipids, blood pressure, systemic oxidative stress, inflammatory biomarkers and enterolignans metabolism: markers of systemic inflammation (C-reactive protein, IL-6, TNF-a) and lipid peroxidation (F2-isoprostanes) were not affected. Cornish et al. (2009), by studying the effects of a flaxseed lignan complex supplementation in subjects (4 or ¼50 years), have found no change in cytokines between men taking flaxseed lignan complex and men taking placebo.

yMean ± SE. Repeated measures ANOVA; means along each treatment followed by different letters are significantly different. zStudent’s t-test.

No differences in plasma nitric oxide concentrations were found between the two intervention periods (Table 6). The release of nitric oxide is one of the factors of endothelial function modulation. Pellegrini et al. (2010), by carrying out an observational study in middle aged and elderly men and postmenopausal women, showed that higher matairesinol intakes in the context of a typical Northern Italian diet are associated to lower vascular inflammation and endothelial disfunction, which could have some implications in cardiovascular diseases (CVDs) prevention. Lee et al. (2004) reported that another plant lignan sesamin induces nitric oxide production in human umbilical vein endothelial cells. Hallund et al. (2006b) have shown that after six weeks of a daily consumption of a lignan complex isolated from flaxseed by postmenopausal women, their plasma concentrations of nitrite and nitrate were not affected. Enterolignans in plasma Table 7 gives the plasma Enl and End concentrations for each participant at each measurement point. Enterolignans concentrations in biological fluids have been used as a biomarker for lignan intake in several studies and enterolactone is regarded as a biomarker of total fiber intake and of a healthy lifestyle (Adlercreutz, 2002; Aubertin-Leheudre et al., 2010; Jacobs et al., 2002). Although the high dietary exposure to lignans during the whole grain-based food was assured by the diet analysis (Table 1), plasma enterolignans concentrations were low. Penalvo et al. (2004) found that plasma Enl and End concentrations were near detection limits. Differences in the different foods bioavailability and in the reliability of the intake measurements should be considered (Lampe, 2003). Milder et al. (2007) found that the relation between lignan intake and plasma End was modulated by age and previous use of antibiotics, whereas for Enl, it was modulated by weight, current smoking and frequency of defecation. Horner et al. (2002) reported that plasma Enl concentrations were associated with age and inversely associated with BMI.

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Table 7. Plasma enterolactone and enterodiol (nmol/L) for each subject at weeks 0, 2, 4 of each treatmenty. Enterolactone

Enterodiol

Whole grain

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Subjects 1 2 3 4 5 6 7 8 9 10 11 12 13

Refined grain

Whole grain

Refined grain

0

2 weeks

4 weeks

0

2 weeks

4 weeks

0

2 weeks

4 weeks

0

2 weeks

4 weeks

n.d. n.d. 2.9 9.7 3.8 2.9 37.1 n.d. n.d. 3.9 n.d. 6.9 n.d.

10.9 n.d. 13.0 10.4 17.3 n.d. 29.2 n.d. n.d. n.d. n.d. n.d. n.d.

8.6 n.d. n.d. 20.1 10.9 6.7 43.3 n.d. n.d. n.d. n.d. 4.9 n.d.

n.d. n.d. 5.1 56.1 12.3 n.d. 3.8 n.d. n.d. n.d. 8.3 n.d. n.d.

8.5 n.d. n.d. 4.7 15.3 n.d. 8.4 n.d. n.d. n.d. 63.9 n.d. n.d.

5.2 n.d. n.d. 7.3 7.0 n.d. 6.4 n.d. n.d. n.d. 9.6 n.d. n.d.

n.d. n.d. n.d. 3.1 n.d. n.d. 8.1 n.d. n.d. n.d. n.d. n.d. n.d.

6.4 n.d. n.d. 12.1 n.d. n.d. 7.8 n.d. 25.3 24.3 n.d. n.d. 7.3

n.d. n.d. n.d. 17.6 n.d. 22.2 6.1 n.d. n.d. 6.8 n.d. n.d. n.d.

n.d. n.d. n.d. 31.0 n.d. 5.2 n.d. n.d. n.d. n.d. n.d. n.d. n.d.

5.1 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. 40.1 n.d. n.d.

n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.

yn.d. – not detectable. Table 8. Effect of whole grain versus refined cereal based foods consumption on urinary lignan excretion (nmol/L)y. 0 Intervention period

Mean ± SE

4 weeks Range

Mean ± SE

Range

Isolariciresinol Whole grain 109.7 ± 19.2 Refined grain 118.5 ± 22.7 p Valuez n.s.

22.0–242.0 47.1–326.3

Whole grain Refined grain p Valuez

55.2 ± 9.1 63.0 ± 20.8 n.s.

6.5–111.9 15.4–301.1

Whole grain Refined grain p Valuez

a

92.46 ± 10.42 146.05 ± 18.80 n.s.

43.4–159.3 41.1–236.6

Lariciresinol 59.78 ± 11.51 56.40 ± 13.56 n.s.

16.8–174.2 11.0–156.9

Figure 1. Hypocholesterolaemic effect of whole grain products. # Student’s t-test respect to baseline, p50.05.

16.9–156.8 6.3–141.0

maintenance of plasma enterolactone concentrations (Borriello et al., 1985; Bowey et al., 2003; Penalvo et al., 2004).

Secoisolariciresinol 43.9 ± 6.1 38.4 ± 8.1 n.s.

9.3–87.8 6.5–105.6

69.1 ± 10.9b 46.4 ± 11.2 n.s.

Dietary lignans and enterolignans in urine

Pinoresinol Whole grain Refined grain p Valuez

77.5 ± 29.5 84.6 ± 30.1 n.s.

n.d.–384.3 15.4–208.7

58.9 ± 16.4 55.7 ± 14.1 n.s.

n.d.–325.8 6.6–173.9

Matairesinol Whole grain Refined grain p Valuez

7.6 ± 0.6 9.4 ± 2.4 n.s.

6.8–12.5 6.8–38.4

10.7 ± 3.6 7.9 ± 0.8 n.s.

6.8–53.6 n.d.–16.5

Enterolactone Whole grain 999.2 ± 604.5 10.0–8215.0 1577.4 ± 663.6 Refined grain 571.2 ± 158.1 12.1–1686.5 1092.4 ± 691.4 p Valuez n.s. n.s.

238.1–9018.0 18.9–9285.3

Enterodiol a

Whole grain 186.1 ± 69.9 Refined grain 188.0 ± 49.9 p Valuez n.s.

19.9–948.8 41.4570.8

762.9 ± 224.4b 347.7 ± 186.1 n.s.

35.0–2471.2 31.9–2508.3

yMean ± SE and range. Data were not normally distributed. Repeated measures ANOVA; means along each treatment followed by different letters are significantly different (p50.05). zStudent’s t-test.

Furthermore, interindividual differences were recorded. Enterolignans have relatively short half-lives and their production relies on colonic bacteria: the composition and activity of the colonic microflora in individuals represent key factors in the

Means and ranges of urinary lignan excretion for the 13 participants in the study are reported in Table 8. There was a wide range in urinary lignan levels and the variability in excretion was great in both treatments, probably due to the short experimental period and the small size of the sample. Dietary lignan differences between and along the treatments were not statistically significant, except for secoisolariciresinol which was observed to increase its concentration from 43.9 ± 6.1 nmol/L at baseline to 69.1 ± 10.9 nmol/L during the whole grain cereal-based foods treatment. For enterolactone, urine levels ranged from 10.0 nmol/L to 9285.3 nmol/L and for enterodiol from 19.9 nmol/L to 2508.3 nmol/L. A significant increase of enterodiol concentrations was observed at the end of the whole grain cereal-based foods treatment compared to the baseline (Table 8). Hallund et al. (2008) showed that a 6-week daily consumption of a low-fat muffin enriched with a lignan complex significantly increase serum Enl concentrations and urinary Enl excretion in healthy postmenopausal women. Frische et al. (2003) reported that urinary lignan excretion increased with flaxseed consumption. Among individuals consuming a Western diet, urinary phytoestrogen excretion can reflect differences in dietary patterns: a variety of fiber-containing foods was shown to contribute to lignan excretion, in particular fruits and grains (Adlercreutz et al., 1987; Lampe et al., 1999).

DOI: 10.3109/09637486.2014.893283

Effects of consumption of whole grain foods rich lignans in healthy postmenopausal women

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In conclusion, 4 weeks consumption of whole grain cerealbased foods rich in lignans have proven to have a moderate cholesterol-lowering effect and an enterodiol excretion increasing effect in healthy postmenopausal women. Our results do not suggest that plant lignans from whole grain products may affect antioxidant and inflammation markers in the same women. However, a limitation of the present study is the relatively small size of the sample and the short experimental period (4 weeks only). Several other factors should also be considered when interpreting metabolic responses to whole grain food consumption such as subjects’ genetical characteristics as well as characteristics connected to the nature of the ingested food, i.e. type of food, its physical structure, its amount and preparation.

Declaration of interest This work was done within the research project QUA.SI.CER financed by MIUR (Italian Ministry for University and Research). The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

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