bluuebunny/crossref_metadata_2025 huggingface dataset:
High resolution longitudinal analysis to evaluate the timing, duration and dynamics of exclusive breastfeeding in the Peruvian Amazon (119.3)
Authors: Ambikapathi Ramya , Kosek Margaret , Olortegui Maribel , Caulfield Laura
Published: June 2021

The duration of exclusive breastfeeding (EBF) is often defined by the time from birth to the first non‐breast milk food/liquid fed (non‐EBF), or it is estimated by calculating the proportion of women at a given infant age who EBF in the previous 24 hr. Others have measured the total days of EBF (personal prevalence), recognizing that although non‐EBF days may occur, extended periods of EBF can be re‐initiated. We estimated and compared these metrics using data from enrollment (median 4 d, IQR: 3, 6) to 180 d among infants enrolled in the Peru MAL‐ED cohort study. Twice weekly surveillance was conducted with caretakers queried about infant feeding patterns in the previous 24 hr. Total of 14,922 household visits and 48,781 child days of nutritional data in the first 180 d were collected among 271 infants. The median duration of EBF (to first non‐EBF) was 19 d (IQR: 7, 63), in contrast to 54 d (IQR: 52, 60) based on prior 24‐hr method. The median total EBF prevalence was 81 d (IQR: 28, 131). Differences are due to the return to EBF after a non‐EBF period. Median number of returns to EBF is 2 (IQR: 1, 4). The first time mothers returned EBF, their infants gained 10.9 d (SE 3.9), and the second time, infants gained 8.1 d (SE 4.1) of EBF. Studies show that longer personal prevalence of EBF positively affects infant health. In settings where women report short gaps in EBF, programs should work with women to return to EBF during the 0‐6 month period. Interventions are likely to influence the duration of these secondary periods of EBF and their quantification should be considered in impact evaluation studies.

Grant Funding Source: Funded by FNIH through grant from BMGF.
Early impact assessment of a large‐scale initiative to improve infant and young child feeding (IYCF) in Bangladesh and Vietnam suggests improvements in IYCF practices and highlights importance of potential to benefit (119.6)
Authors: Menon Purnima , Rawat Rahul , Nguyen Phuong , Saha Kuntal , Kennedy Andrew , Khaled Adiba , Mai Lan , Ruel Marie
Published: June 2021

Alive & Thrive (A&T) aims to improve IYCF through inter‐personal communications (IPC) and mass media (MM) interventions based on robust formative research. In the context of cluster‐randomized impact evaluations in Bangladesh (BD) and Vietnam (VN), and after early process evaluation that established reach and quality, we assessed early impacts of A&T‐intensive (A&T‐I) (IPC + MM), compared to A&T‐non intensive (A&T‐NI) (MM only) on 8 IYCF indicators. Baseline (2010) and mid‐line (2013) survey data [N~2000 children in A&T‐I and A&T‐NI groups in each country] were used to derive double‐difference estimates (DDE) of early impact on IYCF over time and between groups, adjusting for sample clustering. Large and significant early impacts were seen for 5 of 8 IYCF indicators in Bangladesh [early initiation of BF, exclusive BF, minimum dietary diversity (MDD), minimum acceptable diet, and intake of iron‐rich foods]; DDE ranged from 18.7 pp (EBF, p<0.01) to 26 pp (MDD, p<0.01). In VN, early impacts were seen only for EBF (DDE=21.2 pp, p<0.05); for complementary feeding in VN and continued BF in Bangladesh, potential to benefit was limited by high levels at baseline. Conclusions: Well‐designed and well‐implemented large‐scale interventions that combine IPC and MM have great potential to impact IYCF practices in Bangladesh, Vietnam and similar contexts, but impact could be conditional on initial levels of indicators.

Grant Funding Source: Supported by: Bill & Melinda Gates Foundation, through Alive & Thrive, managed by FHI 360
The effect of fluid dairy products on food intake, glycemic and appetite hormone responses in children (120.3)
Authors: Vien Shirley , Patel Barkha , Panahi Shirin , El Khoury Dalia , Luhovyy Bohdan , Hamilton Jill , Anderson G.
Published: June 2021

Dairy intake has been linked to healthier body weight (BW) in children, but the effect of milk consumption on short‐term food intake (FI) has not been explored in this group. We examined the effect of milk compared to other commonly consumed drinks on subjective appetite (SA), FI, glycemia and appetite hormones (AH) in normal weight (NW) and overweight/obese (OWOB) children in two experiments. Exp. 1 compared the effects of pre‐meal and within meal consumption of isocaloric (130 kcal) and isovolumetric (250 mL) drinks of 2% milk, 1% chocolate milk (CM), 1.5% yogurt drink (YD), fruit punch (FP) and water on SA and FI at a pizza meal given 60 min later in NW and OWOB children. In all children, FI was 13 and 9% lower after CM and YD, respectively (P < 0.01), than water. Post‐meal SA was lower after milk than YD (P < 0.01). Exp. 2 compared the effects of pre‐meal and within meal consumption of milk and FP on SA, FI 60 min later, glucose and AH responses in NW and OWOB children. Pre‐meal SA increased and post‐meal SA decreased more after milk than FP (P < 0.05). Meal‐time FI and glucose and insulin AUCs were similar after the drinks and not affected by BW, but AH responses were altered. GLP‐1 AUC was higher after milk than FP and in OWOB compared to NW children (P < 0.03). The post‐prandial drop in ghrelin was greater after milk than FP in OWOB children (‐24 vs. ‐14%, P = 0.06), but similar in NW children after both drinks (‐12 vs. ‐16%, P = 0.58). Thus, pre‐meal and within meal milk consumption stimulates GLP‐1 and leads to greater ghrelin suppression in OWOB children, with no effect on FI.

Grant Funding Source: Supported by Dairy Farmers of Canada
Aerobic fitness protects against ovariectomy associated metabolic dysfunction in rats (120.8)
Authors: Vieira‐Potter Victoria , Scroggins Rebecca , Park Young‐Min , Welly Rebecca , Britton Steve , Koch Lauren , Jenkins Nathan , Padilla Jaume , Thyfault John
Published: June 2021

Ovariectomized (OVX) rodents model human menopause in that they rapidly gain weight and reduce physical activity (PA). How aerobic fitness protects against OVX‐associated metabolic dysfunction is not known. Female rats (n=43) selectively bred for high (HCR) and low intrinsic aerobic fitness (LCR) were maintained under standard conditions from 16‐39 wks of age. Midway, OVX or SHM operations were performed. Insulin sensitivity (via GTT, HOMA) and energy expenditure (EE) (via indirect calorimetry w/ PA monitoring via multidimensional beam breaks) were measured before and 4 wks after surgery. The 4 groups were compared for body mass and composition (DXA), adipose tissue (AT) distribution, brown (BAT), and fasting glucose, insulin, and lipids. HCR were ~30% smaller, had ~70% greater PA, consumed ~10% more energy relative to BW and had ~40% more BAT (all line, p<0.05). Remarkably, HCR were completely protected from OVX‐associated increases in BW, total and visceral AT, and HOMA, all of which increased in LCR (all grp x line int., p<0.01). OVX did not increase energy intake and reduced PA similarly in both lines (grp, p<0.01). Resting (REE) decreased only in LCR, as did relative BAT, which was correlated with REE across groups (r=0.6, p<0.01). Findings suggest that aerobic fitness may protect against OVX‐associated metabolic dysfunction, at least partially via a preservation of REE and BAT.

Grant Funding Source: Supported by University of Missouri Research Council Grant and NIH R01DK088940
Life‐time genistein consumption alters unfolded protein response in mammary glands and tumors, and prevents antiestrogen resistance in rats (121.5)
Authors: Zhang Xiyuan , Hilakivi‐Clarke Leena
Published: June 2021

We have previously observed that life‐time dietary intake of genistein (GEN) prevents development of tamoxifen (TAM) resistance in rat mammary tumor. This study investigated the mechanisms explaining this effect.

Female Sprague‐Dawley rats were supplemented with 0 or 500 ppm GEN before puberty. Mammary carcinogen DMBA was administered at 48 days of age, and four dietary groups were established: lifelong GEN, prepubertal GEN, adult GEN and controls. Rats were then treated with 337 ppm TAM citrate via diet, and those fed GEN lifelong or during adult life were kept on GEN during TAM treatment. GEN was also given again to the rats consuming it at prepuberty and to some control rats. The remaining TAM treated control rats were never fed GEN. Tumors of rats fed GEN during prepuberty or lifelong exhibited reduced resistance to TAM, compared to no GEN controls, whilst adult only GEN intake caused TAM resistance (p<0.001). Mammary cancer recurrence rate was highest in the rats which started consuming GEN during TAM treatment (p<0.001).

Chronic activation of the unfolded protein response (UPR) pathway has been linked to TAM resistance. We found that the active form of ATF6, ATF6 p50, was higher in normal mammary glands of lifelong GEN fed rats than in the controls (p<0.05). mRNA expression of its target genes, Xbp1 and GRP78, were also higher in the lifelong GEN group (p<0.05). However, the levels of GRP78, IRE1α, ATF4 and Beclin were significantly lower in the tumors of lifelong GEN exposed rats compared with adulthood only GEN fed rats (p<0.05).

Thus, lifelong GEN intake may stimulate responsiveness of mammary tumors to TAM by affecting the UPR pathway:members of this pathway were activated in the normal mammary gland and suppressed in the tumors of lifelong GEN consuming rats.

Mammary tumor response to TAM treatment

no GEN control
post‐diagnosis GEN
adult GEN
prepubertal GEN
lifelong GEN

Complete response (%)
54
33
38
56
52

Partial response (%)
8
16
21
21
24

Resistance (%)
38
51
41
23
24

Recurrence (% of complete response)
23
33
7
11
18

Grant Funding Source: Supported by NCI U54CA149147
Major diet sources of gut microbiota metabolites and type 2 diabetes (121.8)
Authors: Li Yanping , Wang Dong , Chiuve Stephanie , Manson JoAnn , Willett Walter , Hu Frank , Qi Lu
Published: June 2021

BACKGROUND: Emerging evidence has implicated gut microbiota in type 2 diabetes (T2D); and recent studies have associated gut microbiota metabolites including choline, betaine and trimethylamine‐N‐oxide (TMAO), with cardiovascular disease, obesity, and other diabetes risk factors. Little is known about the association between the major diet sources of these metabolites and T2D.

OBJECTIVE: The objective was to evaluate the associations of diet sources of gut microbial metabolites, including phosphatidylcholine, other choline‐containing components, and betaine with incident T2D METHODS: We followed 69, 993 women from the Nurses' Health Study (NHS 1980‐2008), 89, 337 women from NHS II (1991‐2009) and 37,481 men from the Health Professionals Follow‐up Study (1986‐2008) who were free of diabetes, cardiovascular disease and cancer at baseline.

RESULTS: We documented in total 14, 370 incident cases of T2D during 18‐28 years of follow‐up in the three cohorts. Comparing to individuals in the lowest quintile of dietary phosphatidylcholine intakes, the multivariate adjusted relative risk (RR; 95% confident interval (CI)) of T2D associated with the highest quintile of intake was 1.33 (1.20‐1.47) in NHS, 1.34 (1.17‐1.53) in NHS II and 1.18 (1.02‐1.37) in HPFS, resulted in a pooled RR of 1.30 (1.21‐1.39%). Dietary free choline, choline from glycerophocholine, and betaine were all consistently associated with reduced risk of T2D, while choline from sphingomyelin associated with increased risk of T2D, with RRs (95% CI) of 0.84 (0.77‐0.91), 0.88 (0.82‐0.94), 0.88 (0.83‐0.94) and 1.11 (1.00‐1.22), respectively, in the pooled analysis of the three cohorts, comparing the highest to the lowest quintiles of intakes.

CONCLUSION: our data provide consistent evidence from the three separate cohorts that diet major sources of gut microbiota metabolites are related to risk of T2D.

Grant Funding Source: CA87969, CA176726, and CA167552 from NIH
Short‐term low zinc intake alters DNA damage and zinc transporter expression without changing plasma zinc (122.2)
Authors: Burke Sarah , Shenvi Swapna , Killilea David , Holland Tai , Sutherland Barbara , Kim Elijah , Shigenaga Mark , King Janet
Published: June 2021

Zinc deficiency continues to be a major concern of international nutrition, yet there are still few sensitive and reliable biomarkers for identifying moderate zinc deficiency or monitoring changes in zinc status. Plasma zinc content is used most frequently, but it is influenced by conditions other than zinc intake and, therefore, is not reliable except when zinc intake is very low. In this study, the sensitivity of leukocytic zinc transporter gene expression and genomic integrity were evaluated in a moderate depletion/repletion study. Eighteen healthy men were provided a low zinc (6 mg/day) diet with added phytate for two weeks followed by an adequate zinc (10 mg/day) diet for four weeks. They then consumed an ad libitum diet while taking a 25mg zinc supplement for three weeks. Leukocyte DNA damage increased (p<0.0001) during the depletion phase, as detected by the Comet Assay. ZIP1, ZIP4, and ZnT1 zinc transporter gene expression was evaluated in isolated leukocytes and measured using qPCR. ZnT1 gene expression increased (p=0.02) during the depletion phase, although total plasma and leukocyte zinc levels did not change. These results suggest that a short‐term, low zinc intake alters genomic integrity and zinc transporter expression, but not plasma zinc. These potential biomarkers may be useful to evaluate zinc deficiency and the effectiveness of zinc interventions in conditions where plasma zinc remains unchanged.

Grant Funding Source: This study was funded by a grant from HarvestPlus.
Low dietary zinc promotes cell stress following blast injury (122.5)
Authors: Scrimgeour Angus , Carrigan Christopher , Urso Maria , van Helden Herman , Joosen Marloes
Published: June 2021

Increased metallothionein (MT) and extracellular matrix metalloprotease (MMP) activity has been documented in skeletal muscle following ischemia/reperfusion injury (I/R). MTs bind zinc (Zn) and MMPs, possibly affecting activation of the Zn‐dependent mTOR pathway and MMP‐dependent tissue remodeling post‐injury. Because dietary Zn can reduce I/R, we evaluated the effects of 5‐weeks of low‐ and adequate Zn diets on MMP and TIMP expression in muscle following exposure to blast. Thirty‐two anesthetized Wistar rats were exposed to explosive blast (18g Semtex; 120kPa incident pressure); 32 rats served as Controls. Soleus muscle was harvested at 48h and 14d post‐blast. qRT‐PCR was used to quantify mRNA. All blast‐exposed rats exhibited transient bradycardia and bradypnea post‐injury. Loss‐of‐consciousness averaged 200 sec. At 48h post‐injury, there was a blast‐induced (P<0.05), and Zn‐responsive (P<0.05) upregulation of MT‐MMP (4.3‐fold), MMP‐2 (3.0‐fold), TIMP‐1 (5.6‐fold) and TIMP‐2 (3.4‐fold). MMP‐3 and MMP‐9 were inhibited by the blast, and were not responsive to Zn‐supplementation. No differences were observed 14d post‐blast. Our results suggest that exposure to blast activates MMPs acutely in skeletal muscle, and this response is attenuated by 14d. Low Zn diets interfere with the MMP/TIMP response in muscle, suggesting that Zn‐supplementation ameliorates blast‐induced cell stress.

Grant Funding Source: Supported by US Army MRMC, US Air Force MSA
Adaptation of iron bioavailability with high phytate diet consumption (122.6)
Authors: Armah Seth , Reddy Manju
Published: June 2021

Phytate is one of the inhibitors of nonheme iron absorption which is of particular concern in developing countries. In this study, we investigated whether individuals adapt to the inhibitory effect of phytate on iron bioavailability. Female subjects with Ferritin < 30µg/L (n=28) were randomized into two groups of 14 after matching for ferritin. Each group consumed either high or low phytate foods that were provided for 8 weeks. Iron bioavailability from a high phytate test meal was measured using area under the curve (AUC) for serum iron at baseline and after the intervention. During the 8 week period, phytate intake increased significantly (p<0.01) in the high phytate (HP) group and decreased significantly (p<0.001) in the low phytate (LP) group. No significant changes were observed in ferritin and transferrin receptor concentrations in both groups. AUC increased significantly (p<0.05) in the HP group (640 to 905 µmol/L) but the decrease (337 to 267 µmol/L) in the LP group was not significant. We found a strong positive correlation between phytate intake and AUC (r=0.68, p<0.0001) and a negative correlation between hepcidin and AUC at post intervention (r= ‐0.48; p=0.011). Our data suggests that iron bioavailability from high phytate meal may improve in individuals who consume a habitual high phytate diet. Further studies on how long term dietary changes affect the regulation of iron absorption are needed.

Grant Funding Source: IFPRI/HarvestPlus
Lycopene supplementation inhibited high‐fat diet‐promoted hepatic tumorigenesis in both wild‐type and beta‐carotene‐9’,10’‐oxygenase knockout mice (123.1)
Authors: IP Blanche , Liu Chun , Smith Donald , von Lintig Johannes , Wang Xiang‐Dong
Published: June 2021

Obesity is associated with increased liver cancer risks, morbidity and mortality. A recent study (Ip et al., 2013) showed that apo‐10’‐lycopenoic acid, a lycopene (LYC) metabolite generated by beta‐carotene‐9’,10’‐oxygenase (BCO2), inhibited carcinogen‐initiated, high‐fat diet (HFD)‐promoted liver inflammation and tumor development. This present investigation examined whether LYC can suppress HFD‐promoted hepatic inflammation and tumorigenesis in BCO2‐knockout (BCO2‐KO) and the respective wild‐type (WT; 129SvJ/SvEvTac) mice. Results showed that 24‐week LYC supplementation (100 mg/kg diet) had similar effects on suppressing HFD‐promoted liver tumor incidence (by 19% vs 20%), number (by 56% vs 55%) and volume (by 96% vs 95%) in WT and BCO2‐KO mice, respectively. LYC chemopreventative effects were associated with reduced pro‐inflammatory signaling (NF‐κB p65, STAT3 phosphorylation; IL‐6 protein), F4/80 gene expression and inflammatory foci (p=0.06) in the livers of WT but not BCO2‐KO mice. On the contrary, protective effects of LYC in BCO2‐KO mice were associated with reduced endoplasmic reticulum stress‐mediated unfolded protein response (IRE1α, PERK signaling pathways) that is linked to increased liver cancer risks. Taken together, this data indicated that LYC can prevent HFD‐promoted hepatic tumorigenesis in mice, but may involve differential mechanisms depending on BCO2 expression.

Grant Funding Source: USDA/ARS grant 1950‐51000‐074S
Nutritional modulation of cardiotoxicity and anti‐cancer efficacy related to doxorubicin chemotherapy by glutamine and n‐3 PUFAs (123.8)
Authors: Xue Hongyu , Ren Wenhua , Wischmeyer Paul
Published: June 2021

Doxorubicin (DOX) has been one of the most effective antitumor agents against a broad spectrum of malignancies. However, DOX‐induced cardiotoxicity forms the major factor limiting the dose escalation of the drug. We here comparatively examined how glutamine and n‐3 PUFAs, when provided individually and in combination, would affect cardiotoxicity and anti‐tumor efficacy related to DOX (cumulative dose 12mg/kg) in a female Fisher rat model bearing mammary adenocarcinoma. Both single glutamine (0.5 g/kg/d) and n‐3 PUFA (EPA+DHA, 0.4g/kg/d) treatments prevented cardiac function deterioration, reducd serum cardiac troponin I levels, attenuated lipid peroxidation and preserved anti‐oxidant enzymatic reserve in the cardiac tissue. Single n‐3 PUFA treatment significantly enhanced anti‐tumor activity of DOX. Intriguingly, providing glutamine and n‐3 PUFAs together did not confer a greater benefit; conversely, individual benefits on cardiotoxicity and anti‐tumor efficacy associated with single treatments were instead partially or completely lost when the nutrients were combined. Both glutamine and n‐3 PUFA have the potential to be developed as novel individual adjuncts for DOX‐based chemotherapy, but may antagonize each other’s effects when combined. This work draws into question the common assumption that there are additive benefits of combinations of nutrients, which are beneficial on an individual basis.

Grant Funding Source: American Society of Parenteral and Enteral Nutrition
Mexican children consuming breakfast and ready‐to‐eat cereals had a higher intake and adequacy of micronutrients than breakfast skippers: ENSANUT 2012 (130.4)
Authors: Villalpando Salvador , De la Cruz Gongora Vanessa , Contreras Manzano Alejandra , Beltran‐Velazquez Filiberto , Hervert‐Hernandez Deisy
Published: June 2021

Mexican children consuming breakfast and ready‐to‐eat cereals had a higher intake and adequacy of micronutrients than breakfast skippers: ENSANUT 2012Salvador Villalpando1, Vanessa De la Cruz Gongora1, Alejandra Contreras Manzano1, Filiberto Beltran‐Velazquez2, Deisy Hervert‐Hernandez21Centro de Investigacion en Nutricion y Salud, Instituto Nacional de Salud Publica, Cuernavaca, México; 2Kellogg Company Mexico, Queretaro, Mexico Studies in children suggest that ready to cereal (RTEC) breakfast eaters are more likely to meet daily nutrient intake guidelines and less likely to be obese. Objective: To examine the nutrient intakes of Mexican children consuming RTEC breakfast, other type of breakfast or breakfast skippers . Methods: Dietary data from children aged 1‐11 years (n=4863) participating in the Mexican National Health and Nutrition Examination Survey (ENSANUT) 2012 were analyzed. Results: Overall, 90% and 86% of children aged 1‐4 and 5‐11 years of age, respectively, ate breakfast. For 1‐4 year old children, energy intakes did not differ among breakfast consumers and breakfast skippers. Children 5‐11 y breakfast consumers, had a higher intake of energy than breakfast skippers (p<0.05). Children who ate breakfast had a higher intake of vitamins A, B2, D, calcium and zinc (p<0.05) than breakfast skippers. Particularly, children who had a breakfast with RTEC had a higher intake of vitamins A, E, B1, B2, B3, B6, folate, iron, calcium and zinc (p<0.05) than children skipping breakfast or consuming other types of breakfast. Conclusion: Children eating breakfast and especially RTEC breakfast had a higher dietary micronutrients intake than breakfast skippers.

Grant Funding Source: Supported by a non‐commited grant of Kellogg Company
Designing, implementing and assessing effectiveness of integrating agriculture and health to improve nutrition outcomes: the evaluative process for the Mama SASHA project (132.5)
Authors: Levin Carol , Grant Frederick , Low Jan , Web‐Girard Aimee , Cole Donald
Published: June 2021

Responding to the call for improved evaluation of agriculture’s impact on nutrition, we describe the evaluation process that shaped the Mama SASHA project from its inception and highlight critical findings at each stage. We started with formative research to clarify how to introduce vitamin A rich orange‐fleshed sweet potato (OFSP) to pregnant women through antenatal health visits and supportive community support, deciding on vouchers for vines. We then developed an impact pathway that informed project monitoring indicators, a first round of operational research (OR) to refine the design of the project, a second round of OR to assess feasibility and acceptability and a household survey and complementary cohort study that will evaluate impact on vitamin A status and health outcomes of pregnant women and their children. In this community, where vitamin A deficiency affects approximately 20% of pregnant women and children under 2 years, the integrated agriculture and health approach was feasible and acceptable among implementers, stakeholders and beneficiaries, reaching 3,281 pregnant or lactating women with vouchers and OFSP vines.
Output and cost savings of community gardens in San Jose, California (132.7)
Authors: Algert Susan , Baameur Aziz
Published: June 2021

The food to feed five billion urban people by 2025 will increasingly be grown within cities themselves, emphasizing the need to allocate more land to community gardens as a source of local fresh produce. This study describes an easy and reliable method community gardeners can use to quantify crop yields and track cost savings associated with their gardens. A convenience sample of 83 community gardeners in San Jose, California, completed a background survey in Spring‐Summer of 2012. On average, the gardener’s age was 57, income was $4,900.00 per month, and 25% had completed college. A representative subset of 10 gardeners weighed produce output of their plots using portable electronic scales at three separate garden sites. Yields and cost savings were tabulated overall for each plot and crop type. The quantity of vegetables grown in excess of what was needed for each household to meet the US Dietary Guidelines was calculated for the four month growing season. Results indicate that community garden practices are similar to biointensive high production farming, producing 0.75 lbs vegetables/sq ft., rather than conventional agricultural practices, producing 0.60 lbs/ sq ft. Gardens produced on average 2.55 lbs/plant and saved $435 per plot for the season. Cost savings are greatest if vertical high value crops such as tomatoes and peppers are grown in community garden plots. A substantial amount of excess produce grown in community gardens is distributed to friends and family. More research is needed to document the social networks receiving excess community garden produce and associated costs savings.
A combination of Scutellaria baicalensis and Acacia catechu extracts for short‐term symptomatic relief of joint discomfort associated with osteoarthritis of the knee (134.2)
Authors: Elam Marcus , Ormsbee Lauren , Campbell Sara , Rahnama Nader , Payton Mark , Brummel‐Smith Ken , Daggy Bruce , Arjmandi Bahram
Published: June 2021

The extracts of Scutellaria baicalensis and Acacia catechu have been shown in previous studies to alleviate joint discomfort, reduce stiffness, and improve mobility by reducing the production of proinflammatory molecules over long periods of supplementation. The acute effects of intake of these extracts have not yet been investigated. Thus, we carried out a one week clinical trial for the purpose of examining the extent to which a natural proprietary blend of S. baicalensis and A. catechu (UP446) decreases knee joint pain, mobility, and biomarkers of inflammation in comparison to naproxen. Seventy‐nine men and women (40‐90 years old) diagnosed as having mild to moderate osteoarthritis (OA) consumed either 500 mg/day of the UP446 supplement or 440 mg/day of naproxen for 1 week in a double‐blind randomized control trial. Pain, knee range of motion (ROM), and overall physical activity were evaluated at the start of treatment and at final. Fasting blood was collected for the determination of serum interleukins 1β and 6, tumor necrosis factor‐α, C‐reactive protein and hyaluronic acid with the use of enzyme‐linked immunosorbant assay. The UP446 group experienced a significant decrease in perceived pain (P = .009) time dependently. Stiffness was significantly reduced by both treatments (P = .002, P = .008, UP446 and naproxen, respectively). Significant increases in mean ROM over time (P = .04) were found in the UP446 group. These findings suggest that UP446 is effective in reducing the physical symptoms associated with knee OA.

Grant Funding Source: Unigen, Inc.
Neuroinflammation and sickness induced by lipopolysaccharide in adult and aged mice are not mitigated by dietary broccoli (134.4)
Authors: Townsend Brigitte , Chen Yung‐Ju , Jeffery Elisabeth , Johnson Rodney
Published: June 2021

Aging is associated with chronic neuroinflammation and a heightened neuroinflammatory response during infection resulting in prolonged sickness. Dietary interventions to reduce neuroinflammation are therefore desirable. Broccoli contains glucoraphanin, which is converted to sulforaphane (SFN) during digestion. SFN activates antioxidants including heme oxygenase 1 (HMOX1) and NAD(P)H quinone oxidoreductase (NQO1) and inhibits production of interleukin‐1 (IL‐1β) by lipopolysaccharide (LPS)‐stimulated microglia. Therefore, we hypothesized that dietary broccoli would support an antioxidant response in the brain and inhibit LPS‐induced neuroinflammation and sickness. Adult and aged mice were fed control diet or control diet with 10% broccoli for 4 wk, and then injected i.p. with saline or LPS. After injection social behavior was assessed at 2, 4, 8, and 24 h; and HMOX1, NQO1, and IL‐1β mRNA were quantified in brain at 24 h. LPS reduced social behavior and increased HMOX1, NQO1, and IL‐1β in adult and aged mice (P<0.04); as expected, in aged mice IL‐1β was higher before LPS (P<0.004), tended to be higher after LPS (P=0.11), and restoration of normal behavior took longer (P<0.03). No significant effects of broccoli consumption were evident. Collectively, the results suggest that dietary broccoli does not affect neuroinflammation or sickness in adult or aged mice.

Grant Funding Source: Supported by NIH R01AG016710
Dietary α‐mangostin exacerbates colitis and adversely alters the gut microbiota in mice (134.7)
Authors: Gutierrez‐Orozco Fabiola , Thomas‐Ahner Jennifer , Berman‐Booty Lisa , Galley Jeffrey , Chitchumroonchokchai Chureeporn , Mace Thomas , Bailey Michael , Clinton Steven , Lesinski Gregory , Failla Mark
Published: June 2021

Ulcerative colitis (UC) is characterized by chronic inflammation of the colon partly due to a dysregulated immune response to the gut microbiota. The use of complementary and alternative medicines among UC patients is prevalent. Despite the absence of clinical evidence, nutraceuticals containing mangosteen, a fruit from Southeast Asia, are marketed as beneficial for gut and immune health. We hypothesized that α‐mangostin (α‐MG), the most abundant xanthone in mangosteen, would ameliorate colonic inflammation. The effect of α‐MG on the gut microbiota of healthy mice was also assessed. Dextran sulfate sodium (DSS) was used to induce colitis in C57BL/6J mice fed AIN‐93 (control) diet or AIN‐93 diet with 0.1% α‐MG. Colitis was more severe in mice fed α‐MG than in controls. Mice fed α‐MG also had greater colonic infiltration of immune cells and colonic and systemic inflammation than controls. Interestingly, non‐DSS treated mice fed α‐MG also had increased colonic infiltration of immune cells and inflammation. Moreover, the gut microbiota of these mice had an increased abundance of Proteobacteria and decreased abundance of Firmicutes and Bacteroidetes. This bacterial profile is reminiscent of that seen in human UC. The exacerbating effect of α‐MG on colitis may be associated with its adverse impact on the gut microbiota. The potential for unintended effects of mangosteen products on gut health merits investigation.

Grant Funding Source: MCC and FIC at OSU and Conacyt Fellowship (Mexico)
Targeted next‐generation sequencing of the 1‐carbon metabolism pathway: in search for novel genetic modulators of choline deficiency‐mediated organ dysfunction (135.4)
Authors: Corbin Karen , Parker Joel , da Costa Kerry‐Ann , Zeisel Steven
Published: June 2021

We previously identified three functional single nucleotide polymorphisms (SNPs) that modulate sensitivity to dietary choline deficiency‐mediated organ dysfunction: CHDH rs12676, MTHFD1 rs2236225 and PEMT rs12325817. We aimed to broaden our understanding of the contribution of genetic aberrations in the 1‐carbon pathway to choline deficiency sensitivity. We performed targeted next‐generation sequencing on the following genes: ABCB4, BHMT, CBS, CHDH, CHKA, CHKB, MTHFD1, MTHFR, MTR, PCYT1A, PCYT1B, PEMT, SHMT1, SLC44A1, SLC5A7. The subjects in our study were divided into the following groups based on their response to a choline deficient diet: 1) did not exhibit symptoms of choline deficiency (n = 13); 2) had fatty liver and elevated liver enzymes (n = 15); 3) had elevated skeletal muscle creatine phosphokinase (n = 9). Although our study was underpowered, we identified a set of SNPs that are potential novel genetic modifiers of sensitivity to choline deficiency (primarily in PEMT and MTHFD1) and to organ‐specific deficiency symptoms (primarily in SLC44A1). Importantly, principal components analysis identified a set of SNPs that differentiated those who were sensitive to dietary choline deficiency vs. those that were not (PC1 p‐value = 0.018). Our results delineate candidate SNPs for differentiating individuals that are sensitive to dietary choline deficiency. These SNPs warrant further investigation.

Grant Funding Source: NIH U24‐CA143848‐03; P30‐CA016086‐37; P50‐CA058223‐19A1 (JP)
Vitamin B12: dietary intake, supplement use and serum concentrations in a cohort of Canadian pregnant women and in umbilical cord blood (135.7)
Authors: Masih Shannon , Plumptre Lesley , Ly Anna , Sohn Kyoung‐Jin , Berger Howard , Lausman Andrea , Croxford Ruth , O'Connor Deborah , Kim Young‐In
Published: June 2021

Optimal maternal intake and blood levels of vitamin B12 play an important role in fetal development and in health and disease of the offspring. Nonetheless, there is a paucity of data of intake and blood levels of B12 in Canadian pregnant women and in cord blood. We assessed dietary and supplemental intakes using a food frequency questionnaire and serum B12 levels in pregnant women between 12‐16 wks gestation (n=342) and at parturition (n=292) and in cord blood (n=259). Mean intake of dietary B12 was 5.2 ± 3.1 µg/d and 5.2 ± 2.7 µg/d in early and late pregnancy, respectively (RDA= 2.6 µg/d). Additionally, 88% reported using a B12‐containing supplement (usual amount 2.6 µg) during early pregnancy and 83% continued supplement use in late pregnancy. Median serum B12 concentrations in early pregnancy, at parturition and in cord blood were 220 (inner quartile range: 167,289) pmol/L, 167 (131,208) pmol/L and 314 (223,466) pmol/L, respectively. All participants had plasma homocysteine levels in the normal range (<13 µmol/L) during pregnancy. The prevalence of suboptimal serum B12 levels (<148 pmol/L) was observed in 17% and 36% of women in early and late pregnancy, respectively. Our data indicate that suboptimal B12 status, assessed by serum B12 levels, exists in Canadian women during pregnancy despite adequate B12 intakes from diet and supplement use. Whether the observed low maternal B12 levels are functionally significant and impact maternal and fetal health outcomes requires further investigation.
Nutritional factors and non‐Hodgkin’s lymphoma survival in an ethnically diverse population: The Multiethnic Cohort Study (136.1)
Authors: Maskarinec Gertraud , Leo Qi Jie , Ollberding Nicholas , Kolonrl Laurence , Wilkens Lynne , Le Marchand Loic
Published: June 2021

With an increasing number of non‐Hodgkin’s lymphoma (NHL) survivors, the possible effect of modifiable health behaviors on prognosis has emerged as a topic of interest. For example, obesity appears to be associated with poorer NHL survival. We examined the association of pre‐diagnostic intake of major food groups assessed by food frequency questionnaire at cohort entry with NHL‐specific survival in the five ethnic groups of the Multiethnic Cohort (MEC). MEC participants free of NHL at cohort entry and diagnosed with NHL during follow‐up (N=1348) were followed through linkages to SEER cancer registries and the National Death Index. Cox proportional hazards regression was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for low vs. high intake of meat, fish, vegetables, fruits, dairy, and legumes in relation to NHL‐specific mortality while adjusting for potential confounders including body mass index. The mean age at diagnosis was 70.6 (range 45‐89) years. During 4.3±3.5 years of follow‐up, 679 deaths including 457 NHL‐specific deaths occurred. Consumption of vegetables, fruits, meat, fish, and whole grains was not related to survival, but 蠅1 daily serving of dairy was associated with higher (HR=1.36, 95%CI=1.09‐1.70) and 蠅0.5 daily serving of legumes with lower (HR=0.66, 95%CI=0.49‐0.87) NHL‐specific mortality. Stratification by ethnicity suggested that these associations were limited to Latinos and Whites and not seen in African Americans, Native Hawaiians, and Japanese Americans. Despite the small number of foods associated with survival, the results suggest that diet may influence NHL outcome, possibly through phytanic acids, calcium, or vitamin D in dairy foods and the anti‐inflammatory action of legumes.

Grant Funding Source: R37 CA 54281 and P01 CA 33619
Human obesity produces an inflammatory milieu in both the serum and colonic mucosa: implications for carcinogenesis (136.6)
Authors: Pfalzer Anna , Leung Keith , Garcia Paloma , Liu Zhenhua , Mason Joel
Published: June 2021

Objective‐ Obesity elevates the risk of colon cancer; however, the molecular mechanisms responsible for this association remain speculative. Our lab has previously demonstrated that murine obesity elevates colonic TNFα and IL‐1β, each of which is known to activate important pro‐carcinogenic signaling pathways. We hypothesized that the low‐grade inflammatory state associated with obesity also exists in the human.

Methods‐ Whole blood and colonic biopsies were collected from obese (BMI 蠅 30) and lean (BMI 蠄 25) human subjects undergoing routine colonoscopy. Serum and colonic cytokines were measured using chemiluminescence. Gene expression levels were measured using real‐time PCR.

Results‐ Serum TNFα was increased 1.5‐fold and IL‐6 was increased approximately 2‐fold in obese subjects compared to lean (p<0.01). Colonic mRNA expression of IL1β was elevated 3.5‐fold in obese subjects compared to lean (p<0.05), whereas expression of TNFα, IL‐6 and IFNγ were not elevated. Protein expression of the cytokines was below the level of detection.

Conclusions‐ In addition to confirming that pro‐inflammatory cytokines are elevated systemically in obese humans, we demonstrated that transcript expression for colonic IL‐1β is elevated as well. This increase in colonic expression of IL‐1β appears to be specific since similar elevations do not exist for other pro‐inflammatory cytokines.

Grant Funding Source: Supported by: U.S.D.A. Pilot Project grant
Attitudes towards weight management in cancer survivors (136.8)
Authors: Zhang Fang Fang , Koch‐Weser Susan , Parsons Susan , Singer Mary Beth , Folta Sara , Erban John , Must Aviva , Roberts Susan , Saltzman Edward
Published: June 2021

A large proportion of cancer patients gain weight following cancer diagnosis and treatment, and tend to maintain an undesirable weight years after treatment completion. Undesirable weight gain has been shown to contribute to poor survival outcomes in several cancers. However, cancer survivors may not perceive weight status as important and thus may not be motivated to manage their weight. We conducted a survey to understand attitudes towards weight management in cancer patients and survivors who attended oncology outpatient clinics at Tufts Medical Center between July and November 2012. Over a half (56.5%) of the 209 subjects (mean age=58.3 years; mean BMI=27.9 kg/m2) indicated that they would like to lose weight, followed by those (34.4%) who would like to gain or maintain weight, and those (9.1%) who did not think about their weight. Old age was negatively associated with the attitudes towards weight loss (OR=0.8, 95% CI: 0.6‐0.9 for five‐year increase in age) while being long‐term survivors (off‐treatment 蠅 5 years vs. on‐treatment) (OR=3.3, 95% CI: 1.3‐8.5) and being overweight or obese (BMI 蠅25 vs. <25 kg/m2) (OR=8.1, 95% CI: 3.8‐17.3) was each positively associated with the attitudes towards weight loss. Our findings indicate that the majority of cancer patients/survivors would like to lose weight. Young, overweight/obese and long‐term survivors might be particularly motivated. Intervention needs to be developed to promote weight management in this at‐risk population.
Alterations in intestinal morphology, histology and permeability with exogenous glucagon‐like peptide 2 and epidermal growth factor treatment promote intestinal adaptation in neonatal intestinal failure (137.2)
Authors: Lim David , Levesque Crystal , Wales Paul , Vine Donna , Borthwick Faye , Nation Patrick , Wizzard Pamela , Josephson Jessica , Sigalet David , Bigam David , Li Julang , Turner Justine
Published: June 2021

Background: The peptide factor, glucagon‐like peptide 2 (GLP‐2), augments intestinal adaptation in adults but its efficacy in neonatal short bowel syndrome (nSBS) is not established. GLP‐2 augments the epidermal growth factor (EGF) receptor pathway, suggesting an interactive role in the maintenance of gut health.

Objective: To study the efficacy of exogenous GLP‐2 and EGF administration, alone and in combination, on intestinal adaptation and function in a translational piglet model of nSBS.

Methods: Neonatal piglets (aged 3‐5 days) received one of 4 treatments (saline (n=3), GLP‐2 (n=3), EGF (n=6) and GLP‐2/EGF (n=3) in combination) for 7 days following a 75% mid‐intestinal resection or no resection (sham control). Structural adaptation was assessed by morphology and histology measures. Jejunal permeability of mannitol and polyethylene glycol (PEG) was assessed using Ussing techniques. A sow‐fed control group (n=6) was also used for comparison.

Results: There was no difference in body weight gain or intestinal length between groups. In the resection group, intestinal weight per length increased with EGF treatment compared to saline treatment. Jejunum villus height increased with EGF or GLP‐2 treatment but not in combination, compared to saline treatment (p<0.0001). Combination therapy decreased both jejunum crypt depth compared to saline treatment and ileum crypt depth compared to GLP‐2 or EGF treatment (p<0.001). GLP‐2 alone reduced jejunal permeability of mannitol (p=0.0007) and PEG (p=0.0054) compared to the sham‐saline group. EGF alone increased the permeability of these markers compared to GLP‐2 treatment.

Conclusions: Altogether, these findings illustrate a role for GLP‐2 and EGF therapy in intestinal adaption and function but perhaps not in combination. The combination of therapies appears to dampen the adaptive response histologically. The alterations in permeability suggest an improvement in barrier function with GLP‐2 and a promotion in mucosal growth with EGF.

Grant Funding Source: Supported by: CIHR, ASPEN
Leptin prevents cognitive impairment in a rat model of postnatal growth restriction (137.4)
Authors: Alexeev Erica , Lönnerdal Bo , Griffin Ian
Published: June 2021

PGR is associated with impaired neurodevelopment, and lower serum leptin in preterm infants. We have demonstrated the same in a rodent model. As leptin is important in CNS myelination, we hypothesized that leptin is causally related to poorer neurodevelopment in PGR. Using our previous model, newborn rats were randomized to litters of 10/dam (N, Normal, n=70) or 18/dam (PGR, n=108) until weaning (d21). Between d8‐14, half the pups in each litter were randomized to 3 ug/kg/d rat leptin s.c., half to PBS. After weaning, a high‐fat rodent chow was fed ad libitum to d75. All rats had glucose tolerance and insulin stimulation tests, as well as cognition (spontaneous alternation in a T‐maze) assessed. PGR rats were 30% smaller than N rats from d5‐21 (p<0.0001). Female PGR rats caught‐up with N rats by d75, but male PGR rats remained 15% smaller. Leptin administration increased serum leptin levels but did not affect growth. In PBS‐treated rats, neurodevelopment was worse in PGR (5.5 ±1.2) than N rats (7.0 ±0.8, p<0.0001). Leptin improved neurodevelopment in PGR (7.0 ±1.0, p<0.0001) but not N rats (7.2 ±1.2, p=NS). PGR rats had improved glucose tolerance (p=0.015) and insulin sensitivity (p=0.0001), but leptin had no effect. Leptin reversed cognitive impairment in rats with PGR, without adverse effects on growth, insulin sensitivity, or glucose tolerance. This model and findings merit further investigation in preterm infants.
Metabolomic profiling of zebrafish and mouse models of fetal alcohol spectrum disorder: antioxidants and neural‐related lipids (137.5)
Authors: Keller Christine , Sepúlveda Marisol , Jannasch Amber , Keller Jonathan , Roumani Ali , Zhou Feng , Brown Paul
Published: June 2021

A comprehensive mechanistic profile of metabolite changes occurring in fetal alcohol spectrum disorder (FASD) has yet to be determined. Using zebrafish embryos exposed to 0 ‐ 3 % ethanol from 2 ‐ 24 hours post‐fertiliation, whole‐embryo extracts were examined using a Thermo Fisher LTQ Orbitrap coupled to an Agilent 1100 for liquid chromatography. From this data, we generated a profile of significantly changed metabolites resulting from ethanol treatment. While many of the metabolites have been identified previously, this approach emphasizes the alterations occurring in antioxidant vitamins A, D, and E as well as massive changes in neural‐related lipids such as phosphatidylserines, ceramide, and sphingosine. Additionally, a mouse model comparing 0, 1, or 2 six‐hour 400 mg/dL ethanol exposures were similarly analyzed. Metabolites from the non‐polar extracts of zebrafish and mice were compared, resulting in six significantly changed, commonly‐identified metabolites. These metabolites included short chain fatty acids, phosphatidic acid, and sulfatide. These metabolite profiles provide a more comprehensive understanding of ethanol‐induced changes during development and may lead to better biomarker identification or novel therapies for FASD.

Grant Funding Source: Indiana Clinical and Translational Sciences Institute
Transgenerational transmission of bone deficits in growth restricted offspring (137.6)
Authors: Romano Tania , Anevska Kristina , Gallo Linda , Tran Melanie , Wark John , Wlodek Mary
Published: June 2021

Uteroplacental insufficiency (UPI) reduces uterine blood flow leading to low birth weight offspring with programmed adult bone deficits. We investigated the effects of UPI on F1 maternal bone in pregnancy and if deficits are passed to F2 using embryo‐transfer (ET).

UPI was induced by bilateral uterine vessel ligation (Restricted, R; Control, C) in rats. One cohort of pregnant F1 C and F1 R rats was culled on embryonic day (E) 20. ET was performed on E1 in a cohort of F1 females, with F2 embryos gestated in Control (C‐in‐C, R‐in‐C) or Restricted (C‐in‐R, R‐in‐R) mothers. Non‐ET offspring were also generated. Growth and pQCT femur analysis was performed.

R F1 females were born 10% lighter than C with shorter femurs, lower bone content, density and strength. These differences were absent in pregnancy. F2 non‐ET offspring were born of normal weight and underwent slowed and accelerated growth without transmission of bone deficits. Day 35 male R‐in‐C and R‐in‐R were heavier with longer femurs, increased bone content and strength compared to C‐in‐C/R. Male R embryo groups had accelerated then slowed growth with increased cortical content at 6 months. Restricted ET females did not develop bone deficits.

Deficits observed in non‐pregnant F1 R females were absent during pregnancy, indicating restoration of normal skeletal adaptations. Bone deficits are not passed on from a growth restricted mother to her offspring.