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author:("bomhoff, Rune")
1.  Effect of genetic polymorphisms involved in folate metabolism on the concentration of serum folate and plasma total homocysteine (p-tHcy) in healthy subjects after short-term folic acid supplementation: a randomized, double blind, crossover study 
Genes & Nutrition  2015;10(3):7.
Data on the effect of combined genetic polymorphisms, involved in folate metabolism, on the concentration of serum folate after folic acid supplementation are scarce. Therefore, we investigated the impact of seven gene polymorphisms on the concentration of serum folate and p-tHcy in healthy subjects after short-term folic acid supplementation. In a randomized, double blind, crossover study, apparently healthy subjects were given either 0.8 mg folic acid per day (n = 46) or placebo (n = 45) for 14 days. The washout period was 14 days. Fasting blood samples were collected on day 1, 15, 30 and 45. Data on subjects on folic acid supplementation (n = 91) and on placebo (n = 45) were used for the statistical analysis. The concentration of serum folate increased higher in subjects with higher age (53.5 ± 7.0 years) than in subjects with lower age (24.3 ± 3.2 years) after folic acid supplementation (p = 0.006). The baseline concentration of serum folate in subjects with polymorphism combination, reduced folate carrier protein, RFC1-80 GA and methylenetetrahydrofolate reductase, MTHFR677 CT+TT, was lower than RFC1-80 AA and MTHFR677 CT+TT (p = 0.002). After folic acid supplementation, a higher increase in the concentration of serum folate was detected in subjects with polymorphism combination RFC1-80 GA and MTHFR677 CC than RFC1-80 GG and MTHFR CT+TT combination (p < 0.0001). The baseline concentration of plasma total homocysteine (p-tHcy) was altered by combined polymorphisms in genes associated with folate metabolism. After folic acid supplementation, in subjects with combined polymorphisms in methylenetetrahydrofolate dehydrogenase, MTHFD1-1958 and MTHFR-677 genes, the concentration of p-tHcy was changed (p = 0.002). The combination of RFC1-80 and MTHFR-677 polymorphisms had a profound affect on the concentration of serum folate in healthy subjects before and after folic acid supplementation.
doi:10.1007/s12263-015-0456-4
PMCID: PMC4353892  PMID: 25758536
Short-term folic acid supplementation; Genetic polymorphisms; Serum folate and p-tHcy concentrations
2.  Feasibility of self-sampled dried blood spot and saliva samples sent by mail in a population-based study 
BMC Cancer  2015;15:265.
Background
In large epidemiological studies it is often challenging to obtain biological samples. Self-sampling by study participants using dried blood spots (DBS) technique has been suggested to overcome this challenge. DBS is a type of biosampling where blood samples are obtained by a finger-prick lancet, blotted and dried on filter paper. However, the feasibility and efficacy of collecting DBS samples from study participants in large-scale epidemiological studies is not known. The aim of the present study was to test the feasibility and response rate of collecting self-sampled DBS and saliva samples in a population–based study of women above 50 years of age.
Methods
We determined response proportions, number of phone calls to the study center with questions about sampling, and quality of the DBS. We recruited women through a study conducted within the Norwegian Breast Cancer Screening Program. Invitations, instructions and materials were sent to 4,597 women. The data collection took place over a 3 month period in the spring of 2009.
Results
Response proportions for the collection of DBS and saliva samples were 71.0% (3,263) and 70.9% (3,258), respectively. We received 312 phone calls (7% of the 4,597 women) with questions regarding sampling. Of the 3,263 individuals that returned DBS cards, 3,038 (93.1%) had been packaged and shipped according to instructions. A total of 3,032 DBS samples were sufficient for at least one biomarker analysis (i.e. 92.9% of DBS samples received by the laboratory). 2,418 (74.1%) of the DBS cards received by the laboratory were filled with blood according to the instructions (i.e. 10 completely filled spots with up to 7 punches per spot for up to 70 separate analyses). To assess the quality of the samples, we selected and measured two biomarkers (carotenoids and vitamin D). The biomarker levels were consistent with previous reports.
Conclusion
Collecting self-sampled DBS and saliva samples through the postal services provides a low cost, effective and feasible alternative in epidemiological studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1275-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1275-0
PMCID: PMC4428002  PMID: 25886002
Dried blood spots; Saliva; Postal service; Carotenoids; Vitamin D
3.  Total antioxidant intake in relation to prostate cancer incidence in the Health Professionals Follow up Study 
Epidemiologic evidence on the association of antioxidant intake and prostate cancer incidence is inconsistent. Total antioxidant intake and prostate cancer incidence has not previously been examined. Using the ferric reducing antioxidant potential (FRAP) assay, the total antioxidant content (TAC) of diet and supplements were assessed in relation to prostate cancer incidence. A prospective cohort of 47,896 men aged 40-75 years was followed from 1986 to 2008 for prostate cancer incidence (N=5,656), and they completed food frequency questionnaires (FFQ) every 4 years. A FRAP value was assigned to each item in the FFQ, and for each individual, TAC scores for diet, supplements and both (total) were calculated. Major contributors of TAC intake at baseline were: coffee (28%), fruit and vegetables (23%) and dietary supplements (23%). In multivariate analyses for dietary TAC a weak inverse association was observed; (highest versus lowest quintiles: 0.91 (0.83-1.00, p-trend=0.03) for total prostate cancer, 0.81 (0.64-1.01, p-trend=0.04) for advanced prostate cancer); this association was mainly due to coffee. No association of total TAC on prostate cancer incidence was observed. A positive association with lethal and advanced prostate cancer was observed in the highest quintile of supplemental TAC intake: 1.28 (0.98-1.65, p-trend<0.01) and 1.15 (0.92-1.43), p-trend=0.04). The weak association between dietary antioxidant intake and reduced prostate cancer incidence may be related to specific antioxidants in coffee, to non-antioxidant coffee compounds, or other effects of drinking coffee. The indication of increased risk for lethal and advanced prostate cancer with high TAC intake from supplements warrants further investigation.
doi:10.1002/ijc.28438
PMCID: PMC4274735  PMID: 23959920
Prostate cancer; Antioxidants; Oxidative stress; Diet; Risk factors
4.  Effects of vitamin C and E supplementation on endogenous antioxidant systems and heat shock proteins in response to endurance training 
Physiological Reports  2014;2(10):e12142.
Abstract
Reactive oxygen and nitrogen species are important signal molecules for adaptations to training. Due to the antioxidant properties of vitamin C and E, supplementation has been shown to blunt adaptations to endurance training. In this study, we investigated the effects of vitamin C and E supplementation and endurance training on adaptations in endogenous antioxidants and heat shock proteins (HSP). Thirty seven males and females were randomly assigned to receive Vitamin C and E (C + E; C: 1000 mg, E: 235 mg daily) or placebo (PLA), and underwent endurance training for 11 weeks. After 5 weeks, a subgroup conducted a high intensity interval session to investigate acute stress responses. Muscle and blood samples were obtained to investigate changes in proteins and mRNA related to the antioxidant and HSP system. The acute response to the interval session revealed no effects of C + E supplementation on NFκB activation. However, higher stress responses to exercise in C + E group was indicated by larger translocation of HSPs and a more pronounced gene expression compared to PLA. Eleven weeks of endurance training decreased muscle GPx1, HSP27 and αB‐crystallin, while mnSOD, HSP70 and GSH remained unchanged, with no influence of supplementation. Plasma GSH increased in both groups, while uric acid decreased in the C + E group only. Our results showed that C + E did not affect long‐term training adaptations in the antioxidant‐ and HSP systems. However, the greater stress responses to exercise in the C + E group might indicate that long‐term adaptations occurs through different mechanisms in the two groups.
Reactive oxygen species are important signal molecules for adaptations to training. Previously vitamin C and E supplements has been shown to blunt adaptations to endurance training. In this study, we investigated the effects of vitamin C and E supplementation and endurance training on adaptations in endogenous antioxidants and heat shock proteins.
doi:10.14814/phy2.12142
PMCID: PMC4254089  PMID: 25293598
Antioxidant enzymes; gene expression; NFκB; stress proteins
5.  Hypervitaminosis A is prevalent in children with CKD and contributes to hypercalcemia 
Background
Vitamin A accumulates in renal failure, but the prevalence of hypervitaminosis A in children with predialysis chronic kidney disease (CKD) is not known. Hypervitaminosis A has been associated with hypercalcemia. In this study we compared dietary vitamin A intake with serum retinoid levels and their associations with hypercalcemia.
Methods
We studied the relationship between vitamin A intake, serum retinoid levels, and serum calcium in 105 children with CKD stages 2–5 on dialysis and posttransplant. Serum retinoid measures included retinol (ROH), its active retinoic acid (RA) metabolites [all-trans RA (at-RA) and 13-cis RA] and carrier proteins [retinol-binding protein-4 (RBP4) and transthyretin (TTR)]. Dietary vitamin A intake was assessed using a food diary.
Results
Twenty-five children were in CKD 2–3, 35 in CKD 4–5, 23 on dialysis and 22 posttransplant; 53 % had vitamin A intake above the Reference Nutrient Intake (RNI) value. Children receiving supplemental feeds compared with diet alone had higher vitamin A intake (p = 0.02) and higher serum ROH (p < 0.001). Notably, increased ROH was seen as early as CKD stage 2. For every 10 ml/min/1.73 m2 fall in estimated glomerular filtration rate (eGFR), there was a 13 % increase in ROH. RBP4 levels were increased in CKD 3–5 and dialysis patients. The lowest ratios of ROH:RBP4 were seen in dialysis compared with CKD 2–3 (p = 0.03), suggesting a relative increase in circulating RBP4. Serum ROH, RBP4 and at-RA were associated with serum calcium. On multivariable analysis RBP4 levels and alfacalcidol dose were significant predictors of serum calcium (model R2 32 %) in dialysis patients.
Conclusions
Hypervitaminosis A is seen in early CKD, with highest levels in children on supplemental feeds compared with diet alone. Serum retinoid levels significantly predict hypercalcemia.
doi:10.1007/s00467-014-2916-2
PMCID: PMC4282719  PMID: 25119682
Vitamin A; Retinol; Retinol binding protein 4 (RBP4); Hypercalcemia; Children
6.  Food items contributing most to variation in antioxidant intake; a cross-sectional study among Norwegian women 
BMC Public Health  2014;14:45.
Background
Fruit and vegetable intake has been found to reduce the risk of cardiovascular disease, certain types of cancer and diabetes mellitus. It is possible that antioxidants play a large part in this protective effect. However, which foods account for the variation in antioxidant intake in a population is not very clear. We used food frequency data from a population-based sample of women to identify the food items that contributed most to the variation in antioxidant intake in Norwegian diet.
Methods
We used data from a study conducted among participants in the Norwegian Breast Cancer Screening Program (NBCSP), the national program which invites women aged 50–69 years to mammographic screening every 2 years. A subset of 6514 women who attended the screening in 2006/2007 completed a food frequency questionnaire (FFQ). Daily intake of energy, nutrients and antioxidant intake were estimated. We used multiple linear regression analysis to capture the variation in antioxidant intake.
Results
The mean (SD) antioxidant intake was 23.0 (8.5) mmol/day. Coffee consumption explained 54% of the variation in antioxidant intake, while fruits and vegetables explained 22%. The twenty food items that contributed most to the total variation in antioxidant intake explained 98% of the variation in intake. These included different types of coffee, tea, red wine, blueberries, walnuts, oranges, cinnamon and broccoli.
Conclusions
In this study we identified a list of food items which capture the variation in antioxidant intake among these women. The major contributors to dietary total antioxidant intake were coffee, tea, red wine, blueberries, walnuts, oranges, cinnamon and broccoli. These items should be assessed in as much detail as possible in studies that wish to capture the variation in antioxidant intake.
doi:10.1186/1471-2458-14-45
PMCID: PMC3902183  PMID: 24433390
Antioxidants; Epidemiology; Nutrition; Fruits; Coffee; Vegetables
7.  A Retinoic Acid—Rich Tumor Microenvironment Provides Clonal Survival Cues for Tumor-Specific CD8+ T Cells 
Cancer research  2012;72(20):5230-5239.
While vitamin A has been implicated in host resistance to infectious disease, little is known about the role of vitamin A and its active metabolite, retinoic acid (RA) in host defenses against cancer. Here, we show that local RA production within the tumor microenvironment (TME) is increased up to 5-fold as compared with naïve surrounding tissue, with a commensurate increase in RA signaling to regionally infiltrating tumor-reactive T cells. Conditional disruption of RA signaling in CD8+ T cells using a dominant negative retinoic acid receptor α (dnRARα) established that RA signaling is required for tumor-specific CD8+ T-cell expansion/accumulation and protective antitumor immunity. In vivo analysis of antigen-specific CD8+ T-cell responses revealed that early T-cell expansion was RA-independent; however, late T-cell expansion and clonal accumulation was suppressed strongly in the absence of RA signaling. Our findings indicate that RA function is essential for the survival of tumor-reactive CD8+ T cells within the TME.
doi:10.1158/0008-5472.CAN-12-1727
PMCID: PMC3766319  PMID: 22902413
8.  Retinoic Acid Signalling Is Activated in the Postischemic Heart and May Influence Remodelling 
PLoS ONE  2012;7(9):e44740.
Background
All-trans retinoic acid (atRA), an active derivative of vitamin A, regulates cell differentiation, proliferation and cardiac morphogenesis via transcriptional activation of retinoic acid receptors (RARs) acting on retinoic acid response elements (RARE).We hypothesized that the retinoic acid (RA) signalling pathway is activated in myocardial ischemia and postischemic remodelling.
Methods and Findings
Myocardial infarction was induced through ligating the left coronary artery in mice. In vivo cardiac activation of the RARs was measured by imaging RARE-luciferase reporter mice, and analysing expression of RAR target genes and proteins by real time RT-PCR and western blot. Endogenous retinoids in postinfarcted hearts were analysed by triple-stage liquid chromatography/tandem mass spectrometry. Cardiomyocytes (CM) and cardiofibroblasts (CF) were isolated from infarcted and sham operated RARE luciferase reporter hearts and monitored for RAR activity and expression of target genes. The effect of atRA on CF proliferation was evaluated by EdU incorporation. Myocardial infarction increased thoracic RAR activity in vivo (p<0.001), which was ascribed to the heart through ex vivo imaging (p = 0.002) with the largest signal 1 week postinfarct. This was accompanied by increased cardiac gene and protein expression of the RAR target genes retinol binding protein 1 (p = 0.01 for RNA, p = 0,006 for protein) and aldehyde dehydrogenase 1A2 (p = 0.04 for RNA, p = 0,014 for protein), while gene expression of cytochrome P450 26B1 was downregulated (p = 0.007). Concomitantly, retinol accumulated in the infarcted zone (p = 0.02). CM and CF isolated from infarcted hearts had higher luminescence than those from sham operated hearts (p = 0.02 and p = 0.008). AtRA inhibited CF proliferation in vitro (p = 0.02).
Conclusion
The RA signalling pathway is activated in postischemic hearts and may play a role in regulation of damage and repair during remodelling.
doi:10.1371/journal.pone.0044740
PMCID: PMC3460971  PMID: 23028599
9.  Stress associated gene expression in blood cells is related to outcome in radiotherapy treated head and neck cancer patients 
BMC Cancer  2012;12:426.
Background
We previously observed that a radiotherapy-induced biochemical response in plasma was associated with favourable outcome in head and neck squamous carcinoma cancer (HNSCC) patients. The aim of the present study was to compare stress associated blood cell gene expression between two sub-groups of HNSCC patients with different biochemical responses to radiotherapy.
Methods
Out of 87 patients (histologically verified), 10 biochemical ‘responders’ having a high relative increase in plasma oxidative damage and a concomitant decrease in plasma antioxidants during radiotherapy and 10 ‘poor-responders’ were selected for gene-expression analysis and compared using gene set enrichment analysis.
Results
There was a significant induction of stress-relevant gene-sets in the responders following radiotherapy compared to the poor-responders. The relevance of the involvement of similar stress associated gene expression for HNSCC cancer and radioresistance was verified using two publicly available data sets of 42 HNSCC cases and 14 controls (GEO GSE6791), and radiation resistant and radiation sensitive HNSCC xenografts (E-GEOD-9716).
Conclusions
Radiotherapy induces a systemic stress response, as revealed by induction of stress relevant gene expression in blood cells, which is associated to favourable outcome in a cohort of 87 HNSCC patients. Whether these changes in gene expression reflects a systemic effect or are biomarkers of the tumour micro-environmental status needs further study.
Trial registration
Raw data are available at ArrayExpress under accession number E-MEXP-2460.
doi:10.1186/1471-2407-12-426
PMCID: PMC3517770  PMID: 23009663
Radiotherapy; HNSCC; Antioxidants; Microarray; GSEA; Cancer
10.  MyD88-dependent TLR1/2 signals educate dendritic cells with gut-specific imprinting properties 
Gut-associated dendritic cells (DC) synthesize all-trans retinoic acid (RA), which is required for inducing gut-tropic lymphocytes. Gut-associated DC from MyD88-/- mice, which lack most TLR signals, expressed low levels of retinal dehydrogenases (Raldh, critical enzymes for RA biosynthesis) and were significantly impaired in their capacity to induce gut-homing T cells. Pre-treatment of extra-intestinal DC with a TLR1/2 agonist was sufficient to induce Raldh and to confer these DC with the capacity to induce gut-homing lymphocytes via a mechanism dependent on MyD88 and JNK/MAPK. Moreover, gut-associated DC from TLR2-/- mice or from mice in which JNK was pharmacologically blocked were impaired in their education to imprint gut-homing T cells, which correlated with a decreased induction of gut-tropic T cells in TLR2-/- mice upon immunization. Thus, MyD88-dependent TLR2 signals are necessary and sufficient to educate DC with gut-specific imprinting properties and contribute in vivo to the generation of gut-tropic T cells.
doi:10.4049/jimmunol.1003740
PMCID: PMC3119749  PMID: 21646294
11.  MyD88 and Retinoic Acid Signaling Pathways Interact to Modulate Gastrointestinal Activities of Dendritic Cells 
Gastroenterology  2011;141(1):176-185.
BACKGROUND & AIMS
Gut-associated dendritic cells (DC) metabolize vitamin A into all-trans retinoic acid (RA), which is required to induce lymphocytes to localize to the gastrointestinal (GI) tract and promotes the differentiation of Foxp3+ regulatory T cells (TREG) and immunoglobulin (Ig)A antibody-secreting cells (IgA-ASC). We investigated whether RA functions in a positive-feedback loop, via DC, to induce its own synthesis.
METHODS
We measured levels of retinoids in intestine tissues from mice and assessed the role of RA in activities of gut-associated DC in cell cultures and mice. We used pharmacologic antagonists to determine the signaling pathways involved in regulation of DC and used MyD88−/− mice to determine the contribution of Toll-like receptor (TLR) signaling in RA-mediated activities of DC.
RESULTS
The concentration of retinoids decreased in a proximal-to-distal gradient along the intestine, which correlated with the activity of gut-specific DC. Importantly, RA regulated the ability of gut-associated DC to produce RA, induce T cells to localize to the GI tract, and generate TREG and IgA secreting cells. RA was sufficient to induce its own production by extra-intestinal DC, in vitro and in vivo. RA-mediated regulation of DC required signaling through the mitogen-activated protein kinase signaling pathway and unexpectedly required MyD88, which has been associated with TLR, interleukin (IL)-1, and IL-18 signaling.
CONCLUSIONS
RA is necessary and sufficient to induce DC to regulate T-cell localization to the GI tract and IgA secretion. These findings indicate crosstalk between the RA receptor and MyD88-dependent TLR signaling pathways.
doi:10.1053/j.gastro.2011.04.010
PMCID: PMC3129445  PMID: 21596042
Inflammation; IBD; immune response; mouse model
12.  A retinoic acid–dependent checkpoint in the development of CD4+ T cell–mediated immunity 
The Journal of Experimental Medicine  2011;208(9):1767-1775.
Immune cell activation induces concurrent temporal and spatial retinoic acid signaling, and CD4+ T cell–specific loss of RA signals reduces effector function, migration, and polarity.
It is known that vitamin A and its metabolite, retinoic acid (RA), are essential for host defense. However, the mechanisms for how RA controls inflammation are incompletely understood. The findings presented in this study show that RA signaling occurs concurrent with the development of inflammation. In models of vaccination and allogeneic graft rejection, whole body imaging reveals that RA signaling is temporally and spatially restricted to the site of inflammation. Conditional ablation of RA signaling in T cells significantly interferes with CD4+ T cell effector function, migration, and polarity. These findings provide a new perspective of the role of RA as a mediator directly controlling CD4+ T cell differentiation and immunity.
doi:10.1084/jem.20102358
PMCID: PMC3171100  PMID: 21859847
13.  Cyclic AMP induces apoptosis in multiple myeloma cells and inhibits tumor development in a mouse myeloma model 
BMC Cancer  2011;11:301.
Background
Multiple myeloma is an incurable disease requiring the development of effective therapies which can be used clinically. We have elucidated the potential for manipulating the cAMP signaling pathway as a target for inhibiting the growth of multiple myeloma cells.
Methods
As a model system, we primarily used the murine multiple myeloma cell line MOPC315 which can be grown both in vivo and in vitro. Human multiple myeloma cell lines U266, INA-6 and the B-cell precursor acute lymphoblastic leukemia cell line Reh were used only for in vitro studies. Cell death was assessed by flow cytometry and western blot analysis after treatment with cAMP elevating agents (forskolin, prostaglandin E2 and rolipram) and cAMP analogs. We followed tumor growth in vivo after forskolin treatment by imaging DsRed-labelled MOPC315 cells transplanted subcutaneously in BALB/c nude mice.
Results
In contrast to the effect on Reh cells, 50 μM forskolin more than tripled the death of MOPC315 cells after 24 h in vitro. Forskolin induced cell death to a similar extent in the human myeloma cell lines U266 and INA-6. cAMP-mediated cell death had all the typical hallmarks of apoptosis, including changes in the mitochondrial membrane potential and cleavage of caspase 3, caspase 9 and PARP. Forskolin also inhibited the growth of multiple myeloma cells in a mouse model in vivo.
Conclusions
Elevation of intracellular levels of cAMP kills multiple myeloma cells in vitro and inhibits development of multiple myeloma in vivo. This strongly suggests that compounds activating the cAMP signaling pathway may be useful in the field of multiple myeloma.
doi:10.1186/1471-2407-11-301
PMCID: PMC3161033  PMID: 21767374
14.  Determination of lipid oxidation products in vegetable oils and marine omega-3 supplements 
Food & Nutrition Research  2011;55:10.3402/fnr.v55i0.5792.
Background
There is convincing evidence that replacing dietary saturated fats with polyunsaturated fats (PUFA) decreases risk of cardiovascular diseases. Therefore, PUFA rich foods such as vegetable oils, fatty fish, and marine omega-3 supplements are recommended. However, PUFA are easily oxidizable and there is concern about possible negative health effects from intake of oxidized lipids. Little is known about the degree of lipid oxidation in such products.
Objective
To assess the content of lipid oxidation products in a large selection of vegetable oils and marine omega-3 supplements available in Norway. Both fresh and heated vegetable oils were studied.
Design
A large selection of commercially available vegetable oils and marine omega-3 supplements was purchased from grocery stores, pharmacies, and health food stores in Norway. The content of lipid oxidation products were measured as peroxide value and alkenal concentration. Twelve different vegetable oils were heated for a temperature (225°C) and time (25 minutes) resembling conditions typically used during cooking.
Results
The peroxide values were in the range 1.04–10.38 meq/kg for omega-3 supplements and in the range 0.60–5.33 meq/kg for fresh vegetable oils. The concentration range of alkenals was 158.23–932.19 nmol/mL for omega-3 supplements and 33.24–119.04 nmol/mL for vegetable oils. After heating, a 2.9–11.2 fold increase in alkenal concentration was observed for vegetable oils.
Conclusions
The contents of hydroperoxides and alkenals in omega-3 supplements are higher than in vegetable oils. After heating vegetable oils, a large increase in alkenal concentration was observed.
doi:10.3402/fnr.v55i0.5792
PMCID: PMC3118035  PMID: 21691461
lipid oxidation; commercially available; vegetable oils; marine omega-3 supplements; screening; peroxide value; alkenal concentration
15.  Supplementation of a western diet with golden kiwifruits (Actinidia chinensis var.'Hort 16A':) effects on biomarkers of oxidation damage and antioxidant protection 
Nutrition Journal  2011;10:54.
Background
The health positive effects of diets high in fruits and vegetables are generally not replicated in supplementation trials with isolated antioxidants and vitamins, and as a consequence the emphasis of chronic disease prevention has shifted to whole foods and whole food products.
Methods
We carried out a human intervention trial with the golden kiwifruit, Actinidia chinensis, measuring markers of antioxidant status, DNA stability, plasma lipids, and platelet aggregation. Our hypothesis was that supplementation of a normal diet with kiwifruits would have an effect on biomarkers of oxidative status. Healthy volunteers supplemented a normal diet with either one or two golden kiwifruits per day in a cross-over study lasting 2 × 4 weeks. Plasma levels of vitamin C, and carotenoids, and the ferric reducing activity of plasma (FRAP) were measured. Malondialdehyde was assessed as a biomarker of lipid oxidation. Effects on DNA damage in circulating lymphocytes were estimated using the comet assay with enzyme modification to measure specific lesions; another modification allowed estimation of DNA repair.
Results
Plasma vitamin C increased after supplementation as did resistance towards H2O2-induced DNA damage. Purine oxidation in lymphocyte DNA decreased significantly after one kiwifruit per day, pyrimidine oxidation decreased after two fruits per day. Neither DNA base excision nor nucleotide excision repair was influenced by kiwifruit consumption. Malondialdehyde was not affected, but plasma triglycerides decreased. Whole blood platelet aggregation was decreased by kiwifruit supplementation.
Conclusion
Golden kiwifruit consumption strengthens resistance towards endogenous oxidative damage.
doi:10.1186/1475-2891-10-54
PMCID: PMC3118331  PMID: 21586177
16.  Intakes of culinary herbs and spices from a food frequency questionnaire evaluated against 28-days estimated records 
Nutrition Journal  2011;10:50.
Background
Worldwide, herbs and spices are much used food flavourings. However, little data exist regarding actual dietary intake of culinary herbs and spices. We developed a food frequency questionnaire (FFQ) for the assessment of habitual diet the preceding year, with focus on phytochemical rich food, including herbs and spices. The aim of the present study was to evaluate the intakes of herbs and spices from the FFQ with estimates of intake from another dietary assessment method. Thus we compared the intake estimates from the FFQ with 28 days of estimated records of herb and spice consumption as a reference method.
Methods
The evaluation study was conducted among 146 free living adults, who filled in the FFQ and 2-4 weeks later carried out 28 days recording of herb and spice consumption. The FFQ included a section with questions about 27 individual culinary herbs and spices, while the records were open ended records for recording of herbs and spice consumption exclusively.
Results
Our study showed that the FFQ obtained slightly higher estimates of total intake of herbs and spices than the total intake assessed by the Herbs and Spice Records (HSR). The correlation between the two assessment methods with regard to total intake was good (r = 0.5), and the cross-classification suggests that the FFQ may be used to classify subjects according to total herb and spice intake. For the 8 most frequently consumed individual herbs and spices, the FFQ obtained good estimates of median frequency of intake for 2 herbs/spices, while good estimates of portion sizes were obtained for 4 out of 8 herbs/spices.
Conclusions
Our results suggested that the FFQ was able to give good estimates of frequency of intake and portion sizes on group level for several of the most frequently used herbs and spices. The FFQ was only able to fairly rank subjects according to frequency of intake of the 8 most frequently consumed herbs and spices. Other studies are warranted to further explore the intakes of culinary spices and herbs.
doi:10.1186/1475-2891-10-50
PMCID: PMC3116467  PMID: 21575177
17.  Blood cell gene expression associated with cellular stress defense is modulated by antioxidant-rich food in a randomised controlled clinical trial of male smokers 
BMC Medicine  2010;8:54.
Background
Plant-based diets rich in fruit and vegetables can prevent development of several chronic age-related diseases. However, the mechanisms behind this protective effect are not elucidated. We have tested the hypothesis that intake of antioxidant-rich foods can affect groups of genes associated with cellular stress defence in human blood cells. Trial registration number: NCT00520819 http://clinicaltrials.gov.
Methods
In an 8-week dietary intervention study, 102 healthy male smokers were randomised to either a diet rich in various antioxidant-rich foods, a kiwifruit diet (three kiwifruits/d added to the regular diet) or a control group. Blood cell gene expression profiles were obtained from 10 randomly selected individuals of each group. Diet-induced changes on gene expression were compared to controls using a novel application of the gene set enrichment analysis (GSEA) on transcription profiles obtained using Affymetrix HG-U133-Plus 2.0 whole genome arrays.
Results
Changes were observed in the blood cell gene expression profiles in both intervention groups when compared to the control group. Groups of genes involved in regulation of cellular stress defence, such as DNA repair, apoptosis and hypoxia, were significantly upregulated (GSEA, FDR q-values < 5%) by both diets compared to the control group. Genes with common regulatory motifs for aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (AhR/ARNT) were upregulated by both interventions (FDR q-values < 5%). Plasma antioxidant biomarkers (polyphenols/carotenoids) increased in both groups.
Conclusions
The observed changes in the blood cell gene expression profiles suggest that the beneficial effects of a plant-based diet on human health may be mediated through optimization of defence processes.
doi:10.1186/1741-7015-8-54
PMCID: PMC2955589  PMID: 20846424
18.  Evaluation of energy and dietary intake estimates from a food frequency questionnaire using independent energy expenditure measurement and weighed food records 
Nutrition Journal  2010;9:37.
Background
We have developed a food frequency questionnaire (FFQ) for the assessment of habitual diet, with special focus on the intake of fruit, vegetables and other antioxidant-rich foods and beverages. The aim of the present study was to evaluate the relative validity of the intakes of energy, food and nutrients from the FFQ.
Methods
Energy intake was evaluated against independent measures of energy expenditure using the ActiReg® system (motion detection), whereas 7-days weighed food records were used to study the relative validity of food and nutrient intake. The relationship between methods was investigated using correlation analyses and cross-classification of participants. The visual agreement between the methods was evaluated using Bland-Altman plots.
Results
We observed that the FFQ underestimated the energy intake by approximately 11% compared to the energy expenditure measured by the ActiReg®. The correlation coefficient between energy intake and energy expenditure was 0.54 and 32% of the participants were defined as under-reporters. Compared to the weighed food records the percentages of energy from fat and added sugar from the FFQ were underestimated, whereas the percentage of energy from total carbohydrates and protein were slightly overestimated. The intake of foods rich in antioxidants did not vary significantly between the FFQ and weighed food records, with the exceptions of berries, coffee, tea and vegetables which were overestimated. Spearman's Rank Order Correlations between FFQ and weighed food records were 0.41 for berries, 0.58 for chocolate, 0.78 for coffee, 0.61 for fruit, 0.57 for fruit and berry juices, 0.40 for nuts, 0.74 for tea, 0.38 for vegetables and 0.70 for the intake of wine.
Conclusions
Our new FFQ provides a good estimate of the average energy intake and it obtains valid data on average intake of most antioxidant-rich foods and beverages. Our study also showed that the FFQs ability to rank participants according to intake of total antioxidants and most of the antioxidant-rich foods was good.
doi:10.1186/1475-2891-9-37
PMCID: PMC2949781  PMID: 20843361
19.  CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation 
Nature immunology  2009;10(11):1193-1199.
Location of embryonic lymph node development is determined by the initial clustering of lymphoid tissue inducer cells. We demonstrate that both CXCL13 and CCL21 attracted E12.5–E14.5 lymphoid tissue inducer cells and that initial clustering exclusively depended on CXCL13. Retinoic acid induced early CXCL13 expression in stromal organizer cells independent of lymphotoxin signaling. Notably, neurons adjacent to the lymph node anlagen expressed enzymes essential for retinoic acid synthesis. Furthermore, stimulation of parasymphathetic neural output in adults led to a retinoic acid receptor-dependent induction of CXCL13 in the gut. Therefore, our data show that initiation of lymph node development is controlled by retinoic acid-mediated expression of CXCL13 and suggest that retinoic acid may be provided by adjacent neurons.
doi:10.1038/ni.1789
PMCID: PMC2771164  PMID: 19783990
20.  The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide 
Nutrition Journal  2010;9:3.
Background
A plant-based diet protects against chronic oxidative stress-related diseases. Dietary plants contain variable chemical families and amounts of antioxidants. It has been hypothesized that plant antioxidants may contribute to the beneficial health effects of dietary plants. Our objective was to develop a comprehensive food database consisting of the total antioxidant content of typical foods as well as other dietary items such as traditional medicine plants, herbs and spices and dietary supplements. This database is intended for use in a wide range of nutritional research, from in vitro and cell and animal studies, to clinical trials and nutritional epidemiological studies.
Methods
We procured samples from countries worldwide and assayed the samples for their total antioxidant content using a modified version of the FRAP assay. Results and sample information (such as country of origin, product and/or brand name) were registered for each individual food sample and constitute the Antioxidant Food Table.
Results
The results demonstrate that there are several thousand-fold differences in antioxidant content of foods. Spices, herbs and supplements include the most antioxidant rich products in our study, some exceptionally high. Berries, fruits, nuts, chocolate, vegetables and products thereof constitute common foods and beverages with high antioxidant values.
Conclusions
This database is to our best knowledge the most comprehensive Antioxidant Food Database published and it shows that plant-based foods introduce significantly more antioxidants into human diet than non-plant foods. Because of the large variations observed between otherwise comparable food samples the study emphasizes the importance of using a comprehensive database combined with a detailed system for food registration in clinical and epidemiological studies. The present antioxidant database is therefore an essential research tool to further elucidate the potential health effects of phytochemical antioxidants in diet.
doi:10.1186/1475-2891-9-3
PMCID: PMC2841576  PMID: 20096093
21.  Pre-radiotherapy plasma carotenoids and markers of oxidative stress are associated with survival in head and neck squamous cell carcinoma patients: a prospective study 
BMC Cancer  2009;9:458.
Background
The purpose of this study was to compare plasma levels of antioxidants and oxidative stress biomarkers in head and neck squamous cell carcinoma (HNSCC) patients with healthy controls. Furthermore, the effect of radiotherapy on these biomarkers and their association with survival in HNSCC patients were investigated.
Methods
Seventy-eight HNSCC patients and 100 healthy controls were included in this study. Follow-up samples at the end of radiotherapy were obtained in 60 patients. Fifteen antioxidant biomarkers (6 carotenoids, 4 tocopherols, ascorbic acid, total antioxidant capacity, glutathione redox potential, total glutathione and total cysteine) and four oxidative stress biomarkers (total hydroperoxides, γ-glutamyl transpeptidase, 8-isoprostagladin F2α and ratio of oxidized/total ascorbic acid) were measured in plasma samples. Analysis of Covariance was used to compare biomarkers between patients and healthy controls. Kaplan-Meier plots and Cox' proportional hazards models were used to study survival among patients.
Results
Dietary antioxidants (carotenoids, tocopherols and ascorbic acid), ferric reducing antioxidant power (FRAP) and modified FRAP were lower in HNSCC patients compared to controls and dietary antioxidants decreased during radiotherapy. Total hydroperoxides (d-ROMs), a marker for oxidative stress, were higher in HNSCC patients compared to controls and increased during radiotherapy. Among the biomarkers analyzed, high levels of plasma carotenoids before radiotherapy are associated with a prolonged progression-free survival (hazard rate ratio: 0.42, 95% CI: 0.20-0.91, p = 0.03). Additionally, high relative increase in plasma levels of d-ROMs (hazard rate ratio: 0.31, 95% CI: 0.13-0.76, p = 0.01) and high relative decrease in FRAP (hazard rate ratio: 0.42, 95% CI: 0.17-0.998, p = 0.05) during radiotherapy are also positively associated with survival.
Conclusions
Biomarkers of antioxidants and oxidative stress are unfavourable in HNSCC patients compared to healthy controls, and radiotherapy affects many of these biomarkers. Increasing levels of antioxidant biomarkers before radiotherapy and increasing oxidative stress during radiotherapy may improve survival indicating that different factors/mechanisms may be important for survival before and during radiotherapy in HNSCC patients. Thus, the therapeutic potential of optimizing antioxidant status and oxidative stress should be explored further in these patients.
doi:10.1186/1471-2407-9-458
PMCID: PMC2813240  PMID: 20025747
22.  Cholesterol Metabolism: the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb▿ †  
Molecular and Cellular Biology  2009;29(10):2716-2729.
Cytochrome P450 oxidoreductase (POR) is the obligate electron donor for all microsomal cytochrome P450 enzymes, which catalyze the metabolism of a wide spectrum of xenobiotic and endobiotic compounds. Point mutations in POR have been found recently in patients with Antley-Bixler-like syndrome, which includes limb skeletal defects. In order to study P450 function during limb and skeletal development, we deleted POR specifically in mouse limb bud mesenchyme. Forelimbs and hind limbs in conditional knockout (CKO) mice were short with thin skeletal elements and fused joints. POR deletion occurred earlier in forelimbs than in hind limbs, leading additionally to soft tissue syndactyly and loss of wrist elements and phalanges due to changes in growth, cell death, and skeletal segmentation. Transcriptional analysis of E12.5 mouse forelimb buds demonstrated the expression of P450s involved in retinoic acid, cholesterol, and arachidonic acid metabolism. Biochemical analysis of CKO limbs confirmed retinoic acid excess. In CKO limbs, expression of genes throughout the whole cholesterol biosynthetic pathway was upregulated, and cholesterol deficiency can explain most aspects of the phenotype. Thus, cellular POR-dependent cholesterol synthesis is essential during limb and skeletal development. Modulation of P450 activity could contribute to susceptibility of the embryo and developing organs to teratogenesis.
doi:10.1128/MCB.01638-08
PMCID: PMC2682028  PMID: 19273610
23.  Diet-induced obesity increases NF-κB signaling in reporter mice 
Genes & Nutrition  2009;4(3):215-222.
The nuclear factor (NF)-κB is a primary regulator of inflammatory responses and may be linked to pathology associated with obesity. We investigated the progression of NF-κB activity during a 12-week feeding period on a high-fat diet (HFD) or a low-fat diet (LFD) using NF-κB luciferase reporter mice. In vivo imaging of luciferase activity showed that NF-κB activity was higher in the HFD mice compared with LFD-fed mice. Thorax region of HFD females displayed fourfold higher activity compared with LFD females, while no such increase was evident in males. In male HFD mice, abdominal NF-κB activity was increased twofold compared with the LFD males, while females had unchanged NF-κB activity in the abdomen by HFD. HFD males, but not females, exhibited evident glucose intolerance during the study. In conclusion, HFD increased NF-κB activity in both female and male mice. However, HFD differentially increased activity in males and females. The moderate increase in abdomen of male mice may be linked to glucose intolerance.
doi:10.1007/s12263-009-0133-6
PMCID: PMC2745749  PMID: 19707810
High-fat diet; Luciferase; Inflammation; Glucose intolerance; Molecular imaging
24.  Anecdotes, data and regulatory modules 
Biology Letters  2006;2(3):431-434.
Beginning in the late 1980s, Eric Davidson's group at Cal Tech developed a modularity hypothesis of developmental gene regulation, showing that in an expanding number of cases, particular aspects of development were governed by compact ‘modules’ of transcription factor binding sites (TFBSs), and that these modules were separable, complex and interconnected. Davidson made no attempt to further generalize the hypothesis, but others took up the idea, transported it out of development and extended it to a general rule of clustering. Despite such misbegotten origins, the ‘extended’ modularity hypothesis—that TFBSs in general tend to come in compact clusters—has been highly productive, yet it has never been challenged with a large, diverse and unbiased dataset to see how universal it actually is. The aim of the present paper is to do so. Applying human–mouse–rat phylogenetic footprinting to neighbourhoods of a diverse set of TFBSs, including both developmental and non-developmental signals, we find that the extended hypothesis holds in at least 93.5% of cases. Based on this particular sample, we found a mean module length of 609 nucleotides containing, on an average, 24.5 presumptive regulatory signals of length greater than 5 and averaging 8.5 nucleotides each.
doi:10.1098/rsbl.2006.0484
PMCID: PMC1686202  PMID: 17148423
regulatory modules; gene expression regulation; transcription factors

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