Search

PDF file - 44K, Supplementary Table S2. Primer sequences for RT-PCR.

Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10′-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9′,10′-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)–promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-κB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress–mediated unfolded protein response (ERUPR), through decreasing ERUPR-mediated protein kinase RNA-activated like kinase–eukaryotic initiation factor 2α activation, and inositol requiring 1α–X-box–binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, β-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression. Cancer Prev Res; 7(12); 1219–27. ©2014 AACR.

PDF file - 61K, Supplementary Figure S2. Inhibition of carcinogen-initiated (DEN), HFD-promoted glucose intolerance by APO10LA. Glucose tolerance test was conducted on 6-8 mice/group and calculated for AUC.

PDF file - 69K, The primer sequences for quantitative real-time PCR

PDF file - 30K, Supplementary Table S1. High-fat diet composition.

Supplementary Table S1: Primers sequences for RT-PCR analysis of liver tissue.

Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10′-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9′,10′-double bond by carotene-9′,10′-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose dependently inhibited cell growth and upregulated sirtuin 1 (SIRT1), a NAD+-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)–promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation [decreased inflammatory foci, TNFα, interleukin (IL)-6, NF-κB p65 protein expression, and STAT3 activation] in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene, and protein expression and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, these data indicate that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation. Cancer Prev Res; 6(12); 1304–16. ©2013 AACR.

PDF file - 48K, Supplementary Figure S1. Chemical structure of lycopene, APO10LA, acyclic retinoic acid and all-trans retinoic acid.

PDF file - 54K

Introduction Women and infants are among the most vulnerable groups for micronutrient deficiencies. Pregnancy micronutrient status can affect birth outcomes and subsequent infants’ growth. Methods We determined the relationship between maternal iron and vitamin A status at delivery using several biomarkers (ferritin, soluble transferrin receptor [sTFR], body iron stores [BIS], hemoglobin and retinol binding protein [RBP]) and birth outcomes (body weight, Z-scores, head circumference, small-for-gestational-age and preterm birth) in rural Uganda. We investigated women who had serum results at the point of delivery and paired them to their infants at birth (n = 1244). We employed multivariable linear and logistic regression, adjusting for clustering at the subcounty level to determine the relationship between maternal micronutrients and birth outcomes. Results After adjusting for relevant factors, we found that maternal iron status (ferritin and BIS) and anemia (hemoglobin) were not significantly associated with the assessed birth outcomes. However, there was a significant association between serum sTFR and preterm births (AOR: 0.67; 95% CI 0.48–0.94). For Vitamin A, we observed a significant positive association between RBP and length-for-age (LAZ) at birth (β = 0.12, p Discussion These findings indicate that the relationship between maternal iron status and birth outcomes needs to be further investigated, because depending on the biomarker used the associations were either in favor of an adverse birth outcome or not significant. Additionally, they confirm that higher maternal RBP levels could be beneficial for birth outcomes. Clinicaltrials.gov as NCT04233944.

We describe the lessons learned in building nutrition capacity through the development and implementation of the first dietetics training program in Malawi., Key Messages We developed the first-ever clinical dietetics program in Malawi to equip students with knowledge, attitudes, and skills in nutrition support, health promotion, and disease prevention at the community and health facility levels.We addressed challenges in curriculum implementation, lack of supervision, and lack of capacity-building resources by using unique approaches and building partnerships with existing programs and professionals.Building a dietitian workforce to serve the needs of the population requires a commitment to funding the program, building research capacity, and developing regulatory and practice guidelines., The current nutrition situation in Malawi, characterized by high rates of malnutrition in communities and hospitals and a rapidly increasing burden of overweight/obesity and diet-related noncommunicable diseases, highlights the urgent need for registered dietitians, who have a proven track record in the prevention and management of all forms of malnutrition and improving patient outcomes. However, dietetics practice has been described as underdeveloped and fragmented in many parts of Africa, exacerbated by a severe and chronic shortage of dietetics professionals and a lack of nutrition and dietetic education programs in most African countries. We share early lessons learned in the development and implementation of the first dietetics program in Malawi. Within 6 years, the program produced 10 graduate dietitians who have filled the first clinical dietitian posts in Malawian public hospitals. This early success can be attributed to the model used to develop and implement the program, which included early stakeholder engagement to define the priority skills and competencies of a Malawian dietitian, the use of internationally recognized training standards, and the development of strategic institutional partnerships that brought together complementary skills and expertise. Furthermore, using existing resources and recruiting students with a nutrition and health background accelerated implementation. The current dietetics curriculum responds to the national nutrition and health policy direction and strategic objectives. Early and sustained government engagement was crucial in creating demand and securing career prospects for graduates. Although still in its infancy, dietitians in Malawi are poised to contribute significantly to alleviating the country's complex nutrition challenges.

In rural Bangladesh, intake of nutrient‐rich foods, such as animal source foods (ASFs), is generally suboptimal. Diets low in nutrients and lacking in diversity put women of reproductive age (WRA) at risk of malnutrition as well as adverse birth outcomes. The objective of this study was to assess the relationship between maternal dietary diversity, consumption of specific food groups and markers of nutritional status, including underweight [body mass index (BMI), Key messages Women's nutrition remains poor in rural Bangladesh, with high rates of underweight, overweight and anaemia.Women's Dietary Diversity Score (WDDS) was not systematically associated with underweight, overweight, or anaemia. This has implications for the widespread use of WDDS as a proxy for the quality of women's diet and nutrition.Consumption of specific food groups, including dark green leafy vegetables (DGLV), eggs and animal source foods (ASFs), is positively associated with women's nutrition.Consumption of ASFs, particularly fish, is especially protective against underweight (fish vs. no fish: odds ratio: 0.8, 95% confidence interval: 0.65–0.99, p

Chronic obstructive pulmonary disease (COPD) and lung cancer share the same etiologic factor, cigarette smoking. Higher consumption of dietary lycopene has been associated with lower risks of COPD and lung cancer in smokers. We investigated whether lycopene feeding protects against COPD and lung cancer in ferrets, a nonrodent model that closely mimics cigarette smoke (CS)-induced chronic bronchitis, emphysema, and lung tumorigenesis in human. We also explored whether the protective effect of lycopene is associated with restoring reverse cholesterol transport (RCT), a key driver in persistent inflammation with CS exposure. Ferrets (4 groups, n = 12–16/group) were exposed to a combination of tobacco carcinogen (NNK) and CS with or without consuming lycopene at low and high doses (equivalent to ∼30 and ∼90 mg lycopene/day in human, respectively) for 22 weeks. Results showed that dietary lycopene at a high dose significantly inhibited NNK/CS-induced chronic bronchitis, emphysema, and preneoplastic lesions, including squamous metaplasia and atypical adenomatous hyperplasia, as compared with the NNK/CS alone (P < 0.05). Lycopene feeding also tended to decrease the lung neoplastic lesions. Furthermore, lycopene feeding significantly inhibited NNK/CS-induced accumulation of total cholesterol, and increased mRNA expression of critical genes related to the RCT (PPARα, LXRα, and ATP-binding cassette transporters ABCA1 and ABCG1) in the lungs, which were downregulated by the NNK/CS exposure. The present study has provided the first evidence linking a protective role of dietary lycopene against COPD and preneoplastic lesions to RCT-mediated cholesterol accumulation in lungs.

Background The public health burden of undernutrition remains heavy and widespread, especially in low-income countries like Nepal. While predictors of undernutrition are well documented, few studies have examined the effects of political will and quality of policy or program implementation on child growth. Methods Data were collected from two nationwide studies in Nepal to determine the relationship between a metric of nutrition ‘governance’ (the Nutrition Governance Index), derived from interviews with 520 government and non-government officials responsible for policy implementation and anthropometry measured for 6815 children in 5556 households. We employed Generalized Estimating Equation (GEE) and multilevel regression models. Results A higher NGI (more effective nutrition governance) is positively associated with height-for-age as well as weight-for-height in children over 2 years of age compared to younger children (HAZ; β = 0.02, p β = 0.01, p 24 months old). Mothers’ education, child’s age, BMI and no fever in the past 30 days were also protective of stunting and wasting. Seven percent and 17% of the overall variance in HAZ and WHZ, respectively, are accounted for by variations across the 21 district locations in which sampled households were located. Mean HAZ differs considerably across districts (intercept = 0.116, p Conclusions These results highlight the importance of effective management of policy-based programming and resource use to bring about nutrition gains on the ground. The NGI explained a non-negligible amount of variation in HAZ and WHZ, which underscores the fundamental role that good governance plays in promoting child nutrition and growth, and the value of seeking to measure it to assist governments in moving policies from paper to practice.

OBJECTIVES: Environmental enteric dysfunction (EED), characterized by altered intestinal permeability/inflammation, microbial translocation, and systemic inflammation (SI), may be a significant contributor to poor growth and micronutrient deficiencies in infants from low-resource setting. The objective of this study was to examine relationships among EED, SI, growth, and iron status in a sample of 6-months old infants from rural Uganda. METHODS: We performed a cross-sectional analysis using a subset of infants (n = 548) enrolled in a birth cohort study conducted in 16 sub-counties across northern and southwestern Uganda. EED was assessed via serum levels of antibodies to the bacterial components flagellin and lipopolysaccharide (LPS); SI was assessed via serum levels of alpha(1)-acid glycoprotein (AGP) and C-reactive protein (CRP); iron status was assessed via serum levels of hemoglobin (Hb), soluble transferrin receptor (sTfR), and ferritin. Associations were assessed using adjusted linear regression analysis. RESULTS: At 6 months, ∼35% of infants were stunted (LAZ < −2), and ∼53% were anemic (Hb 1 g/L) and ∼30% had elevated CRP (>5 mg/L). EED biomarkers were significantly correlated with SI biomarkers (r = 0.142–0.193, P

Background Environmental enteric dysfunction (EED), characterized by altered intestinal permeability/inflammation, microbial translocation, and systemic inflammation (SI), may be a significant contributor to micronutrient deficiencies and poor growth in infants from low-resource settings. Objective We examined associations among EED, SI, growth, and iron status at 6 mo of age. Methods We performed a cross-sectional analysis of 6-mo-old infants (n = 548) enrolled in a Ugandan birth-cohort study (NCT04233944). EED was assessed via serum concentrations of anti-flagellin and anti- LPS immunoglobulins (Igs); SI was assessed via serum concentrations of ɑ1-acid glycoprotein (AGP) and C-reactive protein (CRP); iron status was assessed via serum concentrations of hemoglobin (Hb), soluble transferrin receptor (sTfR), and ferritin. Associations were assessed using adjusted linear regression analysis. Results At 6 mo, ∼35% of infants were stunted [length-for-age z score (LAZ) < −2] and ∼53% were anemic [hemoglobin (Hb) 1 g/L) and ∼30% had elevated CRP (>5 mg/L). EED and SI biomarkers were significantly correlated (r = 0.142–0.193, P

Environmental enteric dysfunction (EED), a subclinical disorder of the small intestine, and poor growth are associated with living in poor water, sanitation, and hygiene (WASH) conditions, but specific risk factors remain unclear. Nested within a birth cohort study, this study investigates relationships among water quality, EED, and growth in 385 children living in southwestern Uganda. Water quality was assessed using a portable water quality test when children were 6 months, and safe water was defined as lacking Escherichia coli contamination. Environmental enteric dysfunction was assessed using the lactulose:mannitol (L:M) test at 12–16 months. Anthropometry and covariate data were extracted from the cohort study, and associations were assessed using linear and logistic regression models. Less than half of the households (43.8%) had safe water, and safe versus unsafe water did not correlate with improved versus unimproved water source. In adjusted linear regression models, children from households with safe water had significantly lower log-transformed (ln) L:M ratios (β: −0.22, 95% confidence interval (CI): −0.44, −0.00) and significantly higher length-for-age (β: 0.29, 95% CI: 0.00, 0.58) and weight-for-age (β: 0.20, 95% CI: 0.05, 0.34) Z-scores at 12–16 months. Furthermore, in adjusted linear regression models, ln L:M ratios at 12–16 months significantly decreased with increasing length-for-age Z-scores at birth, 6 months, and 9 months (β: −0.05, 95% CI: −0.10, −0.004; β: −0.06, 95% CI: −0.11, −0.006; and β: −0.05, 95% CI: −0.09, −0.005, respectively). Overall, our data suggest that programs seeking to improve nutrition should address poor WASH conditions simultaneously, particularly related to household drinking water quality.

Background Adverse birth outcomes, including preterm birth and stunting at birth, have long-term health implications. The relation between adverse birth outcomes and chronic, asymptomatic gastrointestinal inflammation (environmental enteric dysfunction-EED) is poorly understood. Objective We aimed to examine the relation between maternal EED and adverse birth outcomes in a sample of pregnant Ugandan women and their newborn infants. Design We conducted a prospective cohort study in Mukono, Uganda. A total of 258 pregnant women were enrolled at their first prenatal visit (∼18 weeks of gestation). EED was measured by urinary lactulose:mannitol (L:M) ratio and serum concentrations of antibodies to the bacterial components flagellin and LPS. Covariates were obtained from survey data collected at 2 time points. Associations were assessed through the use of unadjusted and adjusted simple linear regression models. Results Complete birth outcome data were recorded for 220 infants within 48 h of delivery. Mean ± SD gestational age was 39.7 ± 2.1 wk, and 7% were born preterm. Mean ± SD length and length-for-age z score (LAZ) at birth were 48.1 ± 3.2 cm and -0.44 ± 1.07, respectively. L:M ratio was not associated with any birth outcome. In adjusted models, higher concentrations of natural log-transformed anti-flagellin immunoglobin G (IgG) and anti-LPS IgG were significantly associated with shorter length of gestation (β: -0.89 wk; 95% CI: -1.77, -0.01 wk, and β: -1.01 wk; 95% CI: -1.87, -0.17 wk, respectively) and with reduced length (β: -0.80 cm; 95% CI: -1.55, -0.05 cm, and β: -0.79 cm; 95% CI: -1.54, -0.04 cm, respectively) and LAZ at birth (β -0.44 z score; 95% CI: -0.83, -0.05, and β: -0.40 z score; 95% CI: -0.79, -0.01, respectively). Conclusion Maternal anti-flagellin and anti-LPS IgG concentrations in pregnancy, but not L:M ratio, were associated with shorter gestation and reduced infant length at birth. Further research on the relation between maternal EED and birth outcomes is warranted.

Background: The potential confounding effect of different amounts and proportions of macronutrients across eating patterns on meal or dietary glycemic index (GI) and glycemic load (GL) value determinations has remained partially unaddressed.Objective: The study aimed to determine the effects of different amounts of macronutrients and fiber on measured meal GI and GL values.Design: Four studies were conducted during which participants [n = 20-22; women: 50%; age: 50-80 y; body mass index (in kg/m2): 25-30)] received food challenges containing different amounts of the variable nutrient in a random order. Added to the standard 50 g available carbohydrate from white bread was 12.5, 25, or 50 g carbohydrate; 12.5, 25, or 50 g protein; and 5.6, 11.1, or 22.2 g fat from rice cereal, tuna, and unsalted butter, respectively, and 4.8 or 9.6 g fiber from oat cereal. Arterialized venous blood was sampled for 2 h, and measured meal GI and GL and insulin index (II) values were calculated by using the incremental area under the curve (AUCi) method.Results: Adding carbohydrate to the standard white-bread challenge increased glucose AUCi (P < 0.0001), measured meal GI (P = 0.0066), and mean GL (P < 0.0001). Adding protein (50 g only) decreased glucose AUCi (P = 0.0026), measured meal GI (P = 0.0139), and meal GL (P = 0.0140). Adding fat or fiber had no significant effect on these variables. Adding carbohydrate (50 g), protein (50 g), and fat (11.1 g) increased the insulin AUCi or II; fiber had no effect.Conclusions: These data indicate that uncertainty in the determination of meal GI and GL values is introduced when carbohydrate-containing foods are consumed concurrently with protein (equal amount of carbohydrate challenge) but not with carbohydrate-, fat-, or fiber-containing foods. Future studies are needed to evaluate whether this uncertainty also influences the prediction of average dietary GI and GL values for eating patterns. This trial was registered at clinicaltrials.gov as NCT01023646.

OBJECTIVES: We aimed to assess prevalence of iron and vitamin A deficiencies in Ugandan mothers and infants using the BRINDA (Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia) adjustment and to ascertain any differences by prevalence of malaria. METHODS: From a prospective birth cohort (N = 5000) conducted in rural Uganda (2014–2016), samples from mothers (n = 1652, at birth) and infants (n = 695, 5–7 m/o) were analyzed for ferritin (FER), soluble transferrin receptor (sTFR), retinol binding protein (RBP), CRP, AGP, hemoglobin (Hb) and malaria. FER, sTFR and RBP were adjusted for inflammation using CRP and AGP. Depleted iron stores were defined as: FER 8.3 mg/L for Fe-deficient erythropoiesis; RBP

BACKGROUND β-Cryptoxanthin (BCX), a provitamin A carotenoid shown to protect against nonalcoholic fatty liver disease (NAFLD), can be cleaved by β-carotene-15,15'-oxygenase (BCO1) to generate vitamin A, and by β-carotene-9',10'-oxygenase (BCO2) to produce bioactive apo-carotenoids. BCO1/BCO2 polymorphisms have been associated with variations in plasma carotenoid amounts in both humans and animals. OBJECTIVES We investigated whether BCX feeding inhibits high refined-carbohydrate diet (HRCD)-induced NAFLD, dependent or independent of BCO1/BCO2. METHODS Six-week-old male wild-type (WT) and BCO1-/-/BCO2-/- double knockout (DKO) mice were randomly fed HRCD (66.5% of energy from carbohydrate) with or without BCX (10 mg/kg diet) for 24 wk. Pathological and biochemical variables were analyzed in the liver and mesenteric adipose tissues (MATs). Data were analyzed by 2-factor ANOVA. RESULTS Compared to their respective HRCD controls, BCX reduced hepatic steatosis severity by 33‒43% and hepatic total cholesterol by 43‒70% in both WT and DKO mice (P

Background Kuwaiti adults have experienced a rapid increase in cardiovascular disease (CVD) and its risk factors. Dietary patterns in the Kuwaiti diet associated with the increasingly higher CVD burden have not been adequately evaluated. Objective The objective of this study was to identify the major dietary patterns in Kuwaiti adults and examine their associations with CVD risk factors. Design This cross-sectional study examined data from the 2008-2009 National Nutrition Survey of the State of Kuwait. Participants/setting The study included 555 Kuwaiti adults aged ≥20 years who completed a 24-hour dietary recall. Main outcome measures The outcome measures included CVD risk factors such as obesity (body mass index), abdominal obesity (waist circumference), elevated blood pressure, dyslipidemia (blood lipid levels), diabetes (glucose and glycated hemoglobin levels), and metabolic syndrome. Statistical analysis Dietary patterns were identified using principal component analysis. The associations between dietary patterns and CVD risk factors were analyzed using survey-weighted multivariable linear and logistic regression models. Results Three dietary patterns were identified: vegetable-rich, fast food, and refined grains/poultry. Younger adults had higher adherence to the fast-food or refined-grains/poultry dietary patterns, whereas older adults had higher adherence to the vegetable-rich dietary pattern. The fast-food dietary pattern was positively associated with body mass index (β=.94, 95% CI 0.08 to 1.79), waist circumference (β=2.05, 95% CI 0.20 to 3.90 cm), and diastolic blood pressure (β=1.62, 95% CI 0.47 to 2.77 mm Hg). The refined grains/poultry dietary pattern was positively associated with plasma glucose levels (β=1.02, 95% CI 1.002 to 1.04 mg/dL [0.056 to 0.058 mmol/L]). Individuals in the highest tertile of the fast-food or refined-grains/poultry dietary patterns had higher odds of metabolic syndrome than those in the lowest tertile. Conclusions The fast-food and refined grains/poultry dietary patterns were associated with high prevalence of CVD risk factors among Kuwaiti adults. The current findings underscore the need for prospective studies to further explore dietary pattern and CVD risk factor relationships among at-risk Kuwait adults.

Cigarette smoke (CS) is an independent risk factor in development of nonalcoholic steatohepatitis (NASH) and fibrosis. Lycopene, a carotenoid naturally occurring in tomatoes, has been shown to be a protective agent against tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced NASH. In the present study using a ferret model we investigated whether CS promotes NASH and whether dietary lycopene can inhibit CS-promoted NASH development, and if so, what potential mechanisms were involved. Ferrets were divided into 4 groups (n=12-16/group): control, NNK/CS exposed, NNK/CS plus low-dose lycopene (2.2 mg/kg BW/day), and NNK/CS plus high-dose lycopene (6.6 mg/kg BW/day) groups, for 26 weeks. Results showed that hepatic steatosis, infiltrates of inflammatory cells, and the number and size of inflammatory foci in liver, together with key genes involved in hepatic fibrogenesis were higher in the NNK/CS group compared to the control group; a lycopene diet reversed these changes to the levels of the control group. Interestingly, a major lycopene cleavage enzyme, beta-carotene 9',10'-oxygenase (BCO2), which recently has been recognized to play metabolic roles beyond cleavage function, was down-regulated by NNK/CS exposure, but this decrease was prevented by lycopene feeding. NNK/CS exposure also downregulated liver expression of antioxidant enzymes and upregulated oxidative stress marker, which were all prevented by lycopene. In conclusion, our results suggest that CS can promote development of NASH and liver fibrosis in ferrets, which is associated with downregulation of BCO2 and impairment of antioxidant system in liver; dietary lycopene may inhibit CS-promoted NASH by preventing suppression of BCO2 and decline in antioxidant network.

Background The utility of glycemic index (GI) values for chronic disease risk management remains controversial. Although absolute GI value determinations for individual foods have been shown to vary significantly in individuals with diabetes, there is a dearth of data on the reliability of GI value determinations and potential sources of variability among healthy adults. Objective We examined the intra- and inter-individual variability in glycemic response to a single food challenge and methodologic and biological factors that potentially mediate this response. Design The GI value for white bread was determined by using standardized methodology in 63 volunteers free from chronic disease and recruited to differ by sex, age (18-85 y), and body mass index [BMI (in kg/m2): 20-35]. Volunteers randomly underwent 3 sets of food challenges involving glucose (reference) and white bread (test food), both providing 50 g available carbohydrates. Serum glucose and insulin were monitored for 5 h postingestion, and GI values were calculated by using different area under the curve (AUC) methods. Biochemical variables were measured by using standard assays and body composition by dual-energy X-ray absorptiometry. Results The mean ± SD GI value for white bread was 62 ± 15 when calculated by using the recommended method. Mean intra- and interindividual CVs were 20% and 25%, respectively. Increasing sample size, replication of reference and test foods, and length of blood sampling, as well as AUC calculation method, did not improve the CVs. Among the biological factors assessed, insulin index and glycated hemoglobin values explained 15% and 16% of the variability in mean GI value for white bread, respectively. Conclusions These data indicate that there is substantial variability in individual responses to GI value determinations, demonstrating that it is unlikely to be a good approach to guiding food choices. Additionally, even in healthy individuals, glycemic status significantly contributes to the variability in GI value estimates. This trial was registered at clinicaltrials.gov as NCT01023646.

Scope β-Cryptoxanthin (BCX) can be cleaved by both β-carotene 15,15'-oxygenase (BCO1) and β-carotene 9',10'-oxygenase (BCO2), generating biological active vitamin A and apocarotenoids. We examined whether BCX feeding could inhibit diethylnitrosamine (DEN)-initiated, highly refined carbohydrate diet (HRCD)-promoted hepatocellular carcinoma (HCC) development, dependent or independent of BCO1/BCO2 activity. Methods and results Two-week-old male wild-type (WT) and BCO1-/- /BCO2-/- double knockout (DKO) mice are given a single intraperitoneal injection of DEN (25 mg kg-1 body weight) to initiate hepatic carcinogenesis. At 6 weeks of age, all animals are fed HRCD (66.5% of energy from carbohydrate) with or without BCX for 24 weeks. BCX feeding increases hepatic vitamin A levels in WT mice, but not in DKO mice that shows a significant accumulation of hepatic BCX. Compared to their respective HRCD littermates, both WT and DKO fed BCX have significantly lower HCC multiplicity, average tumor size, and total tumor volume, and the steatosis scores. The chemopreventive effects of BCX are associated with increased p53 protein acetylation and decreased protein levels of lactate dehydrogenase and hypoxia-inducible factor-1α in tumors. Conclusion This study suggests that BCX feeding may alleviate HRCD-promoted HCC progression by modulating the acetylation of p53, hypoxic tumor microenvironment, and glucose metabolism, independent of BCO1/BCO2.

Aflatoxins are toxic metabolites of Aspergillus moulds and are widespread in the food supply, particularly in low‐ and middle‐income countries. Both in utero and infant exposure to aflatoxin B1 (AFB1) have been linked to poor child growth and development. The objective of this prospective cohort study was to investigate the association between maternal aflatoxin exposure during pregnancy and adverse birth outcomes, primarily lower birth weight, in a sample of 220 mother–infant pairs in Mukono district, Uganda. Maternal aflatoxin exposure was assessed by measuring the serum concentration of AFB1‐lysine (AFB‐Lys) adduct at 17.8 ± 3.5 (mean ± SD)‐week gestation using high‐performance liquid chromatography. Anthropometry and birth outcome characteristics were obtained within 48 hr of delivery. Associations between maternal aflatoxin exposure and birth outcomes were assessed using multivariable linear regression models adjusted for confounding factors. Median maternal AFB‐Lys level was 5.83 pg/mg albumin (range: 0.71–95.60 pg/mg albumin, interquartile range: 3.53–9.62 pg/mg albumin). In adjusted linear regression models, elevations in maternal AFB‐Lys levels were significantly associated with lower weight (adj‐β: 0.07; 95% CI: −0.13, −0.003; p = 0.040), lower weight‐for‐age z‐score (adj‐β: −0.16; 95% CI: −0.30, −0.01; p = 0.037), smaller head circumference (adj‐β: −0.26; 95% CI: −0.49, −0.02; p = 0.035), and lower head circumference‐for‐age z‐score (adj‐β: −0.23; 95% CI: −0.43, −0.03; p = 0.023) in infants at birth. Overall, our data suggest an association between maternal aflatoxin exposure during pregnancy and adverse birth outcomes, particularly lower birth weight and smaller head circumference, but further research is warranted.

Chronic and excessive alcohol consumption leads to the development of alcoholic liver disease (ALD) and greatly increases the risk of liver cancer. Induction of the cytochrome p450 2E1 (CYP2E1) enzyme by chronic and excessive alcohol intake is known to play a role in the pathogenesis of ALD. High intake of tomatoes, rich in the carotenoid lycopene, is associated with a decreased risk of chronic disease. We investigated the effects of whole tomato (tomato powder, TP), partial tomato (tomato extract, TE), and purified lycopene (LYC) against ALD development in rats. Of the three supplements, only TP reduced the severity of alcohol-induced steatosis, hepatic inflammatory foci, and CYP2E1 protein levels. TE had no effect on these outcomes and LYC greatly increased inflammatory foci in alcohol-fed rats. To further support the protective effect of TP against ALD, TP was supplemented in a carcinogen (diethylnitrosamine, DEN)-initiated alcohol-promoted mouse model. In addition to reduced steatosis and inflammatory foci, TP abolished the presence of preneoplastic foci of altered hepatocytes in DEN-injected mice fed alcohol. These reductions were associated with decreased hepatic CYP2E1 protein levels, restored levels of peroxisome proliferator-activated receptor-α and downstream gene expression, decreased inflammatory gene expression, and reduced endoplasmic reticulum stress markers. These data provide strong evidence for TP as an effective whole food prevention strategy against ALD.

Background: The potential impact of prior meal composition on the postprandial glycemic response and glycemic index (GI) and glycemic load (GL) value determinations remains unclear.Objective: We determined the effect of meals that varied in macronutrient composition on the glycemic response and determination of GI and GL values of a subsequent standard test food.Design: Twenty healthy participants underwent 6 test sessions within 12 wk. The subjects received each of 3 isocaloric breakfast meals (i.e., high carbohydrate, high fat, or high protein) on separate days in a random order, which was followed by a standard set of challenges (i.e., white bread and a glucose drink) that were tested on separate days in a random order 4 h thereafter. Each challenge provided 50 g available carbohydrate. Arterialized venous blood was sampled throughout the 2-h postchallenge period. GI, GL, and insulin index (II) values were calculated with the use of the incremental area under the curve (AUCi) method, and serum lipids were determined with the use of standard assays.Results: The consumption of the high-protein breakfast before the white-bread challenge attenuated the rise in the postprandial serum glucose response (P < 0.0001) and resulted in lower glucose AUCi (P < 0.0001), GI (P = 0.0096), and GL (P = 0.0101) values than did the high-carbohydrate and high-fat breakfasts. The high-protein breakfast resulted in a lower insulin AUCi (P = 0.0146) for white bread than did the high-fat breakfast and a lower II value (P = 0.0285) than did the high-carbohydrate breakfast. The 3 breakfasts resulted in similar serum lipid responses to the white-bread challenge.Conclusions: These data indicate that the macronutrient composition of the prior meal influences the glycemic response and the determination of GI and GL values for white bread. Future studies are needed to determine whether the background food macronutrient composition influences mean dietary GI and GL values that are calculated for eating patterns, which may alter the interpretation of the associations between these values and chronic disease risk. This trial was registered at clinicaltrials.gov as NCT01023646.

Sirtuin 1 (SIRT1) has been reported to protect against nonalcoholic fatty liver disease (NAFLD) development. The mechanism of how SIRT1 deacetylase activity affects NAFLD has not been well investigated. The current investigation addressed the causal effect of systemic SIRT1 activity on NAFLD development and the underlying mechanism involved in both liver and mesenteric adipose tissue (MAT). Both SIRT1 homozygous mice ablated the catalytic activity (sirt1Y/Y) and their corresponding wild type littermates (WT) were fed a high fat diet (HFD, 60% calories from fat) for 34weeks. Sirt1Y/Y mice showed significantly higher level of hepatic triglyceride which was accompanied with higher levels of SREBP-1 and SCD1and decreased phosphorylation of LKB1 and AMPK in the liver. Compared with WT mice, mRNA expression of lipogenic genes (lxrα, srebp-1c, scd1 and fas) in the MAT increased significantly in sirt1Y/Y mice. Fatty acid oxidation biomarkers (acox1, acox3, cpt, ucp1, sirt3) in both liver and MAT were comparable between groups. Interestingly, we observed that in sirt1Y/Y mice, the mRNA level of hormone sensitive lipase (hsl), adipose triglyceride lipase (atgl) and perilipin-2 (plin-2), all involved in lipolysis, significantly increased in MAT, but not in epididymal adipose tissue. These changes positively correlated with circulating free fatty acid (FFA) concentrations and higher hepatic mRNA expression of cd36 for FFA uptake. The present study has provided novel evidence to suggest that under HFD-induced metabolic surplus, the lack of SIRT1 catalytic activity promotes release of FFA from MAT and escalate NAFLD by interfering with lipid homeostasis in both liver and MAT.

Sirtuin 1 (SIRT1) has been reported to protect against nonalcoholic fatty liver disease (NAFLD) development. The mechanism of how SIRT1 deacetylase activity affects NAFLD has not been well investigated. The current investigation addressed the causal effect of systemic SIRT1 activity on NAFLD development and the underlying mechanism involved in both liver and mesenteric adipose tissue (MAT). Both SIRT1 homozygous mice ablated the catalytic activity (sirt1Y/Y) and their corresponding wild type littermates (WT) were fed a high fat diet (HFD, 60% calories from fat) for 34weeks. Sirt1Y/Y mice showed significantly higher level of hepatic triglyceride which was accompanied with higher levels of SREBP-1 and SCD1and decreased phosphorylation of LKB1 and AMPK in the liver. Compared with WT mice, mRNA expression of lipogenic genes (lxrα, srebp-1c, scd1 and fas) in the MAT increased significantly in sirt1Y/Y mice. Fatty acid oxidation biomarkers (acox1, acox3, cpt, ucp1, sirt3) in both liver and MAT were comparable between groups. Interestingly, we observed that in sirt1Y/Y mice, the mRNA level of hormone sensitive lipase (hsl), adipose triglyceride lipase (atgl) and perilipin-2 (plin-2), all involved in lipolysis, significantly increased in MAT, but not in epididymal adipose tissue. These changes positively correlated with circulating free fatty acid (FFA) concentrations and higher hepatic mRNA expression of cd36 for FFA uptake. The present study has provided novel evidence to suggest that under HFD-induced metabolic surplus, the lack of SIRT1 catalytic activity promotes release of FFA from MAT and escalate NAFLD by interfering with lipid homeostasis in both liver and MAT.

Previous studies demonstrated that diet-induced obese mice fed a semi-purified high-fat diet (HFD) had greater liver tumorigenesis than mice fed a non-semi–purified diet. Because ingredients present in standard unpurified diets may elicit potential chemopreventive properties that are not present in semi-purified diets, the present study evaluated hepatic tumorigenic effects of dietary fat by replacing it with refined carbohydrates [digestible saccharides; high-carbohydrate diet (HCD)] in a semi-purified diet without altering other components. Two-wk-old C57Bl/6J male mice were randomly injected i.p. with either the liver-specific carcinogen diethylnitrosamine (25 mg/kg body weight) to induce liver cancer or saline as the nontumor control. At age 6 wk, mice with or without cancer initiation were further randomly assigned to an HFD (26% and 60% energy from carbohydrates and fat, respectively) or an HCD (66% and 12% energy from carbohydrates and fat, respectively) and consumed food ad libitum for 24 wk. Results showed that HCD-fed mice had a comparable degree of hepatic tumorigenesis (tumor number and volume) as HFD-fed mice, despite having significantly reduced body weights. HCD feeding induced greater hepatic endoplasmic reticulum (ER) stress-mediated protein kinase RNA-activated–like kinase (PERK) activation and oncogenic interleukin-6/signal transducer and activator of transcription 3 signaling than HFD feeding. HCD-stimulated PERK signaling was associated with elevated expression of prosurvival markers in tumors, including induced protein kinase B activation, increased extracellular signal-regulated kinases 1/2 phosphorylation, and elevated cyclin D1 protein expression. However, HCD-mediated PERK activation in tumors was also positively associated with markers of proapoptosis, which included elevated CCAAT/enhancer-binding protein homology protein expression and increased cleaved caspase-3. HCD-fed mice had greater severity in hepatic steatosis than HFD-fed mice. HCD-induced steatosis exacerbation was associated with increased expression in hepatic de novo lipogenic markers that can promote ER stress. Together, these data indicated that chronic HCD consumption by mice can produce comparable severity of hepatic tumorigenesis as HFD consumption, potentially through upregulating PERK-mediated ER stress.

OBJECTIVES: Reverse cholesterol transport (RCT), which mediates removal of excess cholesterol from peripheral tissues, is a key player in persistent lung inflammation, a common feature of chronic obstructive pulmonary disease (COPD) and lung cancer, after cigarette smoke (CS) exposure. We have previously shown that lycopene, a carotenoid naturally occurring in tomatoes and tomato products, inhibits tobacco carcinogen (NNK)/CS-induced COPD and preneoplastic lesions in lung of ferrets, but the mechanism is unknown. We hypothesize that the protective role of lycopene against NNK/CS-induced COPD and lung preneoplastic lesions is associated with restoring the RCT in ferrets. METHODS: Male ferrets (4 groups, n = 12−16/group) were exposed to combination of NNK and CS with or without lycopene feeding at low (LL) and high (HL) doses (equivalent to ∼30 mg and ∼90 mg lycopene/day in humans, respectively) for 22 weeks. Ferrets in NNK/CS groups were given NNK (50 mg/kg body weight, i.p. injection) once a month for 4 consecutive months, and were exposed to CS for 30 min/day for 22 weeks. The animals were fed lycopene or placebo starting three weeks prior to the NNK injections and continued until the end of the study. RESULTS: NNK/CS exposure significantly increased total cholesterol levels in both plasma and lungs of ferrets (P

OBJECTIVES: β-Cryptoxanthin (BCX), a provitamin A carotenoid, is cleaved by carotenoid cleavage enzymes including β-carotene-15, 15′-oxygenase (BCO1) to generate vitamin A, and β-carotene-9′, 10′-oxygenase (BCO2) which yields bioactive apo-carotenoids. Dietary supplementation of BCX can prevent non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease worldwide. This study aimed to investigate whether BCX-mediated protection against NAFLD proceeds through the liver-mesenteric adipose tissue axis depending on the presence or absence of BCO1/BCO2. METHODS: Six-week-old male wild type (WT) mice (n = 30) and congenic BCO1(−/−)/BCO2(−/−) double KO (DKO) mice (n = 30) were randomly fed either a high-refined carbohydrate diet (HRCD, 66.5% CHO) or HRCD with BCX (10 mg/kg diet) for 24 weeks. RESULTS: Hepatic levels of BCX, but not retinol and retinyl palmitate, were significantly (P

OBJECTIVES: To examine associations among water source, E. coli contamination, and environmental enteric dysfunction (EED) in a cohort of infants participating in the Uganda Birth Cohort Study (UBCS). METHODS: Infants (n = 729) from 16 sub-counties in rural northern and southwestern Uganda were included in this cross-sectional secondary analysis. Water source and other covariate data were derived from the UBCS 6-month visit, which included a compartment bag test (CBT, Aquagenx, Chapel Hill, NC) to measure E. coli contamination of drinking water. Safe water was defined as no E. coli detected. EED was assessed at age 6 months using serum concentrations of antibodies to the bacterial components flagellin and lipopolysaccharide (LPS) via ELISA. EED biomarkers were natural-log transformed; associations were assessed using cluster-robust adjusted linear regression models. RESULTS: Half of infants were female; 95% were breastfeeding at 6 months of age. Most households (72.8%) relied primarily on an improved water source; i.e., piped water, public tap, tubewell/borehole, or protected well. While 2.6% relied primarily on rain water harvesting, 45.1% practiced it to some degree. Per CBT results, 33.5% of households had safe water, with large variations in quality observed by source [source (% with safe water): piped (50.0%), public tap (17.1%), tubewell/borehole (40.5%), protected well (20.8%), unprotected well (33.0%), rain water (68.4%), surface water (31.6%)]. In adjusted linear regression models (controlling for child sex, current breastfeeding status, and household wealth index), infants from households relying primarily on rain water had significantly lower anti-flagellin IgG levels compared to those relying on improved sources, including piped water (P

Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10′-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9′,10′-double bond by carotene-9′,10′-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose dependently inhibited cell growth and upregulated sirtuin 1 (SIRT1), a NAD+-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)–promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation [decreased inflammatory foci, TNFα, interleukin (IL)-6, NF-κB p65 protein expression, and STAT3 activation] in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene, and protein expression and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, these data indicate that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation. Cancer Prev Res; 6(12); 1304–16. ©2013 AACR.

Prior studies assessing the metabolic effects of different types of carbohydrates have focused on their glycaemic response. However, the response of postprandial cardiometabolic risk indicators has not been considered in these studies. The present study assessed postprandial lipid responses to two forms of carbohydrates used as reference foods for glycaemic index determinations, white bread (50 g available carbohydrate) and glucose (50 g), under controlled conditions and with intra-individual replicate determinations. A total of twenty adults (20–70 years) underwent two cycles of challenges with each pair of reference foods (four challenges/person), administered in a random order on separate days under standard conditions. Serum lipids (total cholesterol, LDL-cholesterol, HDL-cholesterol, TAG and NEFA), glucose and insulin were monitored for 5 h post-ingestion. Oral glucose resulted in greater glycaemic and insulinaemic responses than white bread for the first 90 min and a greater subsequent decline after 120 min (P =0·0001). The initial decline in serum NEFA concentrations was greater after the oral glucose than after the white bread challenge, as was the rebound after 150 min (P =0·001). Nevertheless, the type of carbohydrate had no significant effect on postprandial total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations. Following an initial modest rise in TAG concentrations in response to both challenges, the values dropped below the fasting values for oral glucose but not for the white bread challenge. These data suggest that the type of carbohydrate used to determine the glycaemic index, bread or glucose, has little or modest effects on postprandial plasma cholesterol concentrations. Differences in TAG and NEFA concentrations over the 5 h time period were modest, and their clinical relevance is unclear.

Linoleic acid (LA) and α-linolenic acid (ALA) are essential fatty acids that play an important role in modulation of T cell proliferation. The effects of consuming novel soybean oils varying in LA:ALA ratios on T cell proliferation and inflammatory responses were assessed in older adults. Eighteen participants (>50 y old) with elevated cholesterol concentrations (3.37-4.14 mmol/L LDL cholesterol) consumed 5 experimental diets in random order for periods of 35 d. Each diet contained 30% of energy as fat, two-thirds of which was high-oleic acid soybean oil (HiOleic-SO), soybean oil (SO), low-SFA soybean oil (LoSFA-SO), hydrogenated soybean oil (Hydrog-SO), or low-ALA soybean oil (LoALA-SO), resulting in LA:ALA ratios of 2.98, 8.70, 9.69, 15.2, and 18.3, respectively. Participants had higher proliferative responses to phytohemagglutinin (PHA) compared with baseline following consumption of SO (26%; P 10 (Hydrog-SO and LoALA-SO). Post-diet intervention, LA:ALA ratios correlated with proliferative responses to PHA (r = -0.87; P = 0.05). An optimal proliferative response was observed at an LA:ALA ratio of 8.70, with an inverse correlation between proliferative response and LA:ALA ratios >8.70. These effects were independent of changes in the production of PGE(2), inflammatory cytokines, or cytokines involved in growth of lymphocytes. These data suggest that the LA:ALA ratio modulates the proliferative ability of T lymphocytes, which may be due to subtle changes in fatty acid composition of the phospholipids in immune cells.

The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine-threonine kinase that functions as a critical regulator of inflammatory pathways by up-regulating production of inflammatory cytokines. The present study aims to fill the gap in knowledge regarding the involvement of TPL2 in the mechanism of alcohol-induced hepatic inflammation.Male TPL2(-/-) knockout (TPL2KO) mice and TPL2(+/+) wild-type (WT) mice were group pair-fed with Lieber-DeCarli liquid ethanol diet (EtOH diet, 27% energy from EtOH) or control diet (ctrl diet) for 4 weeks. Both histological and molecular biomarkers involved in the induction of hepatic inflammation by alcohol consumption were examined.Consumption of the EtOH diet in WT mice lead to a significant induction of TPL2 mRNA expression as compared with WT mice fed ctrl diet. A significant induction in inflammatory foci and steatosis was also observed in WT mice fed EtOH diet. The deletion of TPL2 significantly reduced inflammatory foci in the liver of mice consuming both ctrl and EtOH diets as compared to their respective WT controls. This reduction was associated with suppression of hepatic inflammatory gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) and macrophage marker F4/80. In addition, histological analysis of livers revealed that TPL2 deletion resulted in reduced steatosis in both ctrl (significant) and EtOH (non-significant) diet-fed mice as compared to their respective WT controls.The demonstration that TPL2 deletion attenuates alcohol-induced hepatic inflammation provides evidence of a novel role for TPL2 in the pathogenesis of ALD.