bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost‐effectiveness of Mama‐SASHA: a project to improve health and nutrition through an integrated orange‐fleshed sweetpotato production and health service delivery model
Authors: Self Julie , Webb Girard Amy , McFarland Deborah , Grant Frederick , Low Jan , Cole Donald , Levin Carol
Published: June 2021

The Mama‐SASHA project aims to improve the health and nutrition of pregnant/lactating women and children <2 years through an integrated orange‐fleshed sweetpotato (OFSP) and health service strategy in Western Kenya. We analyzed the cost effectiveness from a societal perspective. We estimated the incremental cost‐effectiveness ratio (ICER) of the intervention, which includes OFSP vouchers provided at antenatal care (ANC) visits, nutrition education, and pregnant women's clubs, compared to status quo ANC services. Effectiveness data from a quasi‐experimental study were used to estimate DALYs associated with changes in vitamin A deficiency, stunting, wasting, anemia, diarrhea, and mortality for children <2 years and their mothers. We used ingredients based micro‐costing to estimate economic costs of agriculture, health and community interventions, including opportunity costs of labor for health workers, community volunteers and participants.
Net economic cost over three years was US @445,151. 77 DALYs were averted per year, mostly attributable to improvements in stunting and anemia. The ICER was US @1,919 per DALY averted, which is two times Kenya's GDP per capita (@994 per person) and meets cost‐effectiveness criteria set by WHO. Benefits not convertible into DALY's include improved sweetpotato yield, food security, extension services and nutritional knowledge.
Phytochemical Characterization, Anti‐inflammatory and Lipolytic Activities of Pistachio Hulls, Skins, and Kernels
Authors: Grace Mary , Esposito Debora , Timmers Michael , Lila Mary Ann
Published: June 2021

Anti‐inflammatory, antioxidant, and lipolytic properties of pistachio hull, skin, and kernel extracts were evaluated here. All pistachio fractions reduced nitric oxide (NO) levels in Lipopolysaccharide (LPS)‐induced RAW 264.7 mouse macrophage cell line, at 50 µg/mL. Hulls polar fraction inhibited the LPS‐induced intracellular reactive oxygen species (ROS) to basal levels. Total phenolic contents of pistachio polar extracts represent 37%, 26% and 5% for hulls, skin and kernels, respectively; that is, the phenolic concentration in hulls, was significantly higher than skins and kernels. Hull polar subfractions indicated reductions in mRNA expression levels for the inflammatory markers Cox‐2 and IL‐6 up to 40% and 25%, respectively. LC‐ESI‐MS and NMR analyses of hull polar components showed the presence of quercetin and myricitin galloyl glucopyranosides, quercetin glucuronide, quercetin glucopyranoside, 1,5‐di‐galloyl‐2,3 hexahydroxy‐diphenoly‐scyllo‐quercitol, tri‐galloyl quinoic acid, tri‐galloyl glucopyranoside and gallic acid as main constituents. Assays with 3T3L1 mouse adipocytes demonstrated that all pistachio fractions decreased lipid accumulation up to 17%, with skin non‐polar fraction most active. GC‐MS analysis of the non‐polar fractions indicated that linoleic acid (C18:2) represents a predominant fatty acid in the skin tissue. Our results indicate that pistachio and its bioactive molecules present therein decrease inflammatory biomarkers as well as inhibit lipid accumulation. Results support the potential of pistachio to inhibit biomarkers associated with inflammation and obesity. Also, pistachio hulls represent a rich source of polyphenol antioxidant components.
Nutrient Sources in the Diets of Rural Tanzanian Children 9‐24 Months and Local Pathways to Nutrient Adequacy
Authors: Bauck Aubrey , Patil Crystal , Mduma Estomih , Svensen Erling , Caulfield Laura
Published: June 2021

As part of the MAL‐ED study, a cohort of 231 children living near Haydom, TZ was followed twice weekly to characterize morbidity, diet, growth and development. From 9‐24 mo, a 24‐hr recall was administered monthly to quantify food, energy and nutrient intakes. Here we identify foods and beverages contributing to energy, macro‐ and micronutrient intakes, and evaluate local pathways to improve child dietary intakes. On average, energy, carbohydrate, and protein intakes are sufficient according to WHO guidelines, but fat and selected micronutrient intakes (vit C, vit A, iron, zinc, calcium) are low. The two most important foods in the diet of children 9‐15 months are stiff maize porridge and milk, contributing to energy (45% porridge; 25% milk), carbohydrate (55% porridge; 11% milk), protein (31% porridge, 41% milk), and fat intakes (20% porridge; 59% milk). Top sources of micronutrients are vegetable broths (vit C: okra relish, cabbage, pumpkin or moringa leaf broth), milk (vit A: 67%; calcium: 90%; zinc: 30%), and stiff maize porridge (iron: 60%; zinc: 41%). Porridge and milk continue to be important from 16‐24 mo, but sources of vit A and vit C expand due to increased diet diversity. Days with adequate nutrient intakes were related to the type of food mixed into a child's porridge. Adequate intakes of iron and zinc were more likely to include beans, pumpkin, or a meat mixed into their porridge, or for zinc to include millet rather than maize porridge. Adequate vitamin A intake days were more likely to include porridge with a vegetable (sweet potato, pumpkin) or a leafy broth, and adequate vitamin C intake days included oranges or sweet potatoes.[MAL‐ED is funded by BMGF, NIH/FIC/FNIH]
Civil Conflict and Child Health in Africa: An Instrumental Variables Approach
Authors: Darrouzet‐Nardi Amelia
Published: June 2021

This study examined the linkages between civil conflict and child health in Africa during the period 1992‐2013. Civil insecurity is endemic in some parts of Africa, and non‐existent in other parts. In affected areas, civil conflict shapes the food system through disruption of trade routes, looting, displacement of farmers, and land tenure insecurity. Using a collection of the Demographic and Health Survey (DHS) for 28 countries, merged spatially and temporally with the Armed Conflict Location and Event Dataset (ACLED), I estimated the impact of civil insecurity on mortality risk, heights and weights for over 700,000 children born between 1992 and 2013. For statistical identification in face of measurement error and endogeneity concerns for the civil conflict data, I used geographic variables as instruments for civil conflict risk, and mother fixed‐effects to compare sibling pairs. The results indicate that child mortality risk is increased with exposure to violent conflict during the year before birth and during the year of birth. Being exposed to conflict during the year of birth is especially detrimental for children living in rural areas. Conflict exposure has adverse effects on future child height and weight attainment, and these effects differ depending on the child's geographic location. Findings are robust to the inclusion of child and household controls, country and mother fixed‐effects, and region‐specific time trends. This study builds on previous work which estimates the human health impact of civil insecurity, utilizing a newly constructed database which merges child health information with conflict incident reports at a fine spatial resolution across a long time frame and vast geographic area. This study was supported by a U.S. Borlaug Fellowship in Global Food Security.
The cAMP Responsive Element Binding Protein H Links Metabolic Inflammation with Hyperlipidemia in Hepatic Insulin Resistance
Authors: Zhao Miaoyun , Tong Xuedong , Su Qiaozhu
Published: June 2021

Insulin resistant is commonly associated with both increased circulating levels of tumor necrosis factor‐alpha (TNF‐alpha) and hepatic overproduction of very low density lipoproteins (VLDL). The cAMP responsive binding protein H (CREBH) is a transcription factor whose expression is induced by proinflammatory cytokines. In this study, our objective was to investigate the role of CREBH in mediating lipogenic diet induced hyperlipoproteinemia in the insulin resistance rodent models. By using the wild type and CREBH‐null mouse models combined with fatty acid gavage and TNF‐alpha treatment, we demonstrated that depletion of CREBH reduced both mRNA and protein expression of apolipoprotein B (apoB), a key structure protein in VLDL particle. In vitro, transient expression of CREBH cDNAs in McA cells induced significant increase of apoB mRNA and protein expression and VLDL secretion which indicated the positive regulatory impact of CREBH on apoB biosynthesis. Furthermore, treating McA cells with TNF‐alpha activated CREBH and increased apoB protein level. Challenging the CREBH‐null mice with a dose of long chain fatty acid through gavage or TNF‐alpha treatment failed to stimulate apoB expression and the subsequent VLDL secretion which resulted in hepatic steatosis. Insulin treatment synergized the effect of CREBH on VLDL secretion which may be a contributing factor in insulin resistance induced hyperlipidemia. In conclusion, these data demonstrated that CREBH is the molecular link that mediates inflammatory cytokine signaling to overproduction of VLDL in hepatic insulin resistance. This novel finding provides new mechanistic insight in inflammatory cytokine induced hyperlipidemia in metabolic diseases
Thymoquinone inhibits TNF‐α‐induced pro‐inflammatory mediators in Rheumatoid arthritis synovial fibroblasts in vitro
Authors: Umar Sadiq , Hedaya Omar , Agere Solomon , Ahmed Salahuddin
Published: June 2021

Rheumatoid arthritis (RA) is an autoimmune disease in which cytokine such as tumor necrosis factor‐α (TNF‐α), activate synovial fibroblast (FLS) that results in inflammation and activate joint destruction. In this study using RA‐FLS, we investigate the efficacy of thymoquinone (TQ), a phytochemical found in Nigella sativa, in inhibiting TNF‐α induced proinflammatory mediators. RA‐FLS were pretreated with TQ (1–5 µM) for 2 hours followed by TNF‐α stimulation (30 mins or 24 hours). Conditioned medium was used for the quantification of IL‐6 and IL‐8 by ELISA and cell lysates were prepared for the analysis of adhesion molecule (ICAM‐1 and VCAM‐1) and mitogen‐activated protein kinases. Pretreatment of TQ inhibited the ability of TNF‐α to induce IL‐6 and IL‐8 production in RA synovial fibroblasts in a dose‐dependent manner (p<0.01). We also observed a marked inhibition in TNF‐α induced ICAM‐1 and VCAM‐1 expression by TQ (p<0.01). Evaluation of the signaling pathways using the inhibitors of p38(SB203580), JNK(SP600125),ERK(PD98059) and AKT (LY294001) showed that p38 and JNK played an important role in regulating TNF‐α induced IL‐6 and IL‐8 production, whereas p38 and AKT were involved in regulating ICAM‐1 and VCAM‐1 expression by TNF‐α stimulation in RA‐FLS (p<0.05). TQ was found to selectively inhibit TNF‐induced phosphorylation of p38 and JNK in a dose‐dependent manner. The results of the study show that TQ interferes with TNF‐α signaling pathways to regulate IL‐6 and IL8 production, and ICAM‐1/VCAM‐1 expression in RA‐FLS. Thus,TQ may be of potential therapeutic value in regulating inflammation and synovial invasion in RA.
Impact of Diet and Genetic Induced Obesity on the Stool Metabolome of Tumor Prone Mice
Authors: Nesbeth Paula‐Dene , Pfalzer Anna , Iyer Lakshmanan , Parnell Laurence , Liu Zhenhua , Mason Joel , Crott Jimmy
Published: June 2021

Obesity is associated with an increased risk of colorectal cancer. It is unclear whether this association is driven by metabolic interactions and adaptations to chronic high fat “Western Diet” exposure or excess adiposity. To expound on this association, we characterized the stool metabolome of tumor‐prone Apc1638N made obese by high fat (HF) feeding or the presence of an obesogenic mutation (DbDb). Untargeted metabolomic profiling of stool identified 415 metabolites. Forty‐nine metabolites were significantly altered in HF mice and 41 metabolites in Dbdb mice compared to LF mice (P<0.05). Five metabolites were significantly lower in both comparisons to LF mice: arachidic acid, adenosine, caproic acid, 2‐oxindole‐3‐acetate, tyrosyl‐glycine. Pathway analysis showed changes pyruvate metabolism and gluconeogenesis (adj. P<0.05) identified by significant decreases in lactate and malate in HF compared to LF mice. Sphingosine, sphinganine, and secondary bile acid, lithocholate, were significantly reduced in Dbdb mice compared to LF indicating possible shifts in sphingolipid and bile acid metabolism. Differences in metabolite abundances in stool may identify novel biomarkers for diagnosis, and targets for treatment and prevention of obesity‐induced colorectal cancer.
Relationships between Fathers' Feeding Practices and Preschool Children's Beverage Intake
Authors: Lora Karina , Hubbs‐Tait Laura , Ferris Ann , Anderson Michael
Published: June 2021

Paternal feeding practices and child beverage intake have seldom been examined together. Low‐income fathers (n=92; median age=34 yrs; 53% African‐American, 47% Hispanic) provided demographics, responded to Preschooler Feeding and the Comprehensive Feeding Practices Questionnaires, and completed a quantitative child beverage intake questionnaire. Analyses of variance, the Kruskal‐Wallis test, and Pearson's correlation were used for comparisons. Child's median age was 4 years; 88% lived with fathers. Feeding practices scores (1=never, 5=always) were: Difficulty in child feeding 2.5±0.8, concern about child being overweight 1.7±0.8, use of food to calm child 1.8±0.8, concern about child being underweight 2.0±0.9; and use of food as reward 2.9±1.0. Average daily intake (fl. oz) of total sugar‐sweetened beverages (SSB) was 11.9±15.6, fruit juice 8.4±6.7, juice drinks 4.8±6.1, soda 2.3±3.3, sports drinks 1.6±4.4. Difficulty in child feeding was negatively correlated with child water intake (r=–0.21) and positively correlated with flavored milk intake (r=0.25). Use of food to calm child was positively correlated with child juice drink intake (r=0.24). Use of food as reward was positively correlated with total child SSB (r=0.26), juice drinks (r=0.23), and flavored milk (r=0.28). Identifying links between minority fathers' feeding practices and children's SSB intake provides needed information on the influence of this understudied group of parents.
Docosahexaenoic Acid Status of Pregnant and Lactating Women in Coastland, Lakeland and Inland of China
Authors: Zhou Yu‐bo , Wang Linlin , Ge Hua , Li You , Li Hong‐tian , Liu Jian‐meng
Published: June 2021

Objectives: We aimed to assess the docosahexaenoic acid (DHA) status in Chinese pregnant and lactating women, since there has been lack of reliable data during the past decade in China.

Methods: A cross‐sectional study was conducted in coastland (Weihai), lakeland (Yueyang) and inland (Baotou) of China from May to July 2014. 1210 women who were at the 2nd trimester (17±2 wks), the 3rd trimester (39±2 wks) or lactating (42±7 d postpartum) were enrolled equally from the three regions. Dietary DHA was assessed via an iPad‐based food frequency questionnaire. Fatty acid profiles were assayed by capillary gas chromatography; DHA levels were expressed as a percentage by weight of total fatty acids.

Results: The overall median DHA intake was 17.5 (IQR: 7.0‐41.8) mg/d, and the highest was in coastland (27.8 mg/d), followed by lakeland (19.4 mg/d) and the lowest in inland (9.0 mg/d). The mean plasma DHA was 2.24±0.70; the highest was also in coastland (2.66), followed by lakeland (2.22) and the lowest in inland (1.86). The erythrocyte DHA was 6.17±1.49, which also declined from coastland to inland; corresponding levels were 6.91, 6.25 and 5.37. The trend tests across three regions for DHA intake and the levels of DHA in plasma and erythrocyte were all significant (p values <.0001).

Conclusion

The DHA intake is substantially inadequate compared to the authoritative recommendation. However, in comparison to other populations in literature, plasma and erythrocyte DHA for Chinese women in coastland and lakeland ranks higher, and for inland at medium level.
The Effects of Hypogonadism and Conjugated Linoleic Acid on Regional Adipose Tissue and Fatty Acid Composition in Male Guinea Pigs
Authors: Santosa Sylvia , Yang Susan , Weiler Hope , DeGuire Jason , Agellon Sherry
Published: June 2021

Background

Aging in men is associated with gains in body fat, which are due in part to the age‐related decline in testosterone. Conjugated linoleic acid (CLA) has been consistently shown to reduce body fat or fat gain in animal models through a similarly suggested mechanism as testosterone. Therefore, CLA may counteract the progressive body fat gain that occurs with testosterone decline.

Objectives.

To determine whether CLA modulates changes in body fat, regional fat distribution and adipose tissue fatty acid composition in hypogonadal male guinea pigs.

Methods.

Male, retired breeder guinea pigs (n=40, 70‐72 wk) were block randomized by weight into 4 groups: 1) SHAM/ CTRL, 2) SHAM/ CLA diet (1%), 3) Orchidectomy (ORX)/ CTRL diet, 4) ORX/ CLA diet. Dual‐energy x‐ray absorptiometry scans were performed at baseline and 16 wk to analyze body composition. Visceral and subcutaneous adipose fatty acids were extracted and methylated for gas chromatography (GC) analysis to determine fatty acid composition.

Results.

In ORXCTRL guinea pigs, percent body fat increased by 6.1% and percent lean mass decreased by 6.7 % over the 16 wks while no significant changes in percent body composition were observed in ORXCLA guinea pigs. Guinea pigs fed CLA diet gained less % total body fat and % upper and lower body fat than those fed CTRL regardless of surgical treatment. Regional adipose tissue of fatty acid composition showed that it was reflective of dietary fatty acids.

Conclusion

Hypogonadism in male guinea pigs results in increased fat mass and decreased lean mass. CLA is effective in reducing fat gain and maintaining lean mass in both hypogonadal and intact guinea pigs.
Metabolic Syndrome and Hepatic Steatosis is Reduced in C57BL/6J Mice Fed High‐fat Diets Supplemented with Soy Isoflavones
Authors: Luo Ting , Smith Sarah , Zhao Bingxin , Hamiton‐Reeves Jill , Sullivan Debra , Shay Neil
Published: June 2021

The effect of soy isoflavones on metabolic syndrome and hepatic lipid metabolism was investigated in male C57BL/6J mice fed a high‐fat diet (HF), and HF plus soy isoflavone supplement Novasoy (NS, 0.2%, w/w) diet for 10 weeks. Compared to HF, NS‐fed mice, despite no changes in food intake, had reduced percent weight gain over ten weeks (37±2.2% vs. 45±2.4%), reduced blood glucose levels (276±49 vs. 352±55 vs. mg/dL), reduced serum resistin (4.20±0.68 vs. 5.95±0.46 pg/mL), and reduced leptin (10.5 ±1.89 vs. 21.9±1.25 pg/mL (all p<0.05). In addition, NS consumption prevented hepatic lipid accumulation as determined by histological analyses. Hepatic gene expression was measured and confirmed that intake of NS up‐regulated mRNA levels related to hepatic lipid oxidation, including ACOX‐1 and CPT1‐α. We followed these findings with an in vitro study in which HepG2 cells were induced to accumulate intracellular lipid by exposure to oleic acid followed by treatment with the isoflavone genistein. Genistein treatment at 5μmol/L ameliorated relative intracellular lipid accumulated as measured by oil red O staining (1.0 ± 0.09 vs. 0.85 ± 0.01, p<0.05). We conclude that soy isoflavones have potential to act as an agent to ameliorate symptoms of metabolic syndrome and steatohepatitis.
The effect of EGCG and EGCG nanoparticles on body weight and body composition in LDL receptor null mice
Authors: zu yujiao , zhang jia , nie shufang , wang shu
Published: June 2021

Objective

We successfully synthesized epigallocatechin‐3‐gallate (EGCG) encapsulated nanoparticles (Enano), and incorporated macrophage‐targeting ligands on the surface of Enano (L‐Enano). The objective of this study is to investigate the effect of EGCG, Enano and L‐Enano on body weight, food intake and body composition of LDL receptor null mice (LDLr‐/‐ mice).

Method: Male LDL r‐/‐ mice were fed with an atherogenic diet and received intravenously administration of 1×PBS, EGCG, Enano, or L‐Enano dissolved in 1×PBS at EGCG dose 25 mg/kg body weight for 22 weeks. Food intake and body weight were measured weekly by manual weighing using an electronic laboratory balance, body composition was measured at week 0,10 and 22 using EchoMRI Body Composition Analyzer.

Results: Food intake was similar among all groups. As compared to 1×PBS group, all treatment groups decreased body weight, body fat mass and body fat percentage. L‐Enano compared to Enano decreased body fat percentage. Mice treated with EGCG had less body weight and body fat mass than mice treated with Enano or L‐Enano.

Conclusion

LDLr‐/‐ mice treated with free EGCG lost more body weight and body fat mass than mice treated with EGCG nanoparticles.
Effects of Oral Aged Garlic Extract (AGE) on Indicators of Diabetes and Oxidative Stress in Streptozotocin‐Induced Diabetic Rats
Authors: Thomson Martha , Al‐Qattan Khaled , J.S. Divya , Ali Muslim
Published: June 2021

The anti‐diabetic and antioxidant effects of oral administration of aged garlic extract (AGE) were studied in diabetic rats. Diabetes was induced by IP injection of streptozotocin (60mg/kg, STZ), and a fasting blood sugar >300 mg/dl indicated diabetes. AGE (Wakunaga‐Kyolic, USA) was administered orally at a dose of 600 mg/kg daily for 8 weeks. Diabetic rats were divided into 2 groups, diabetic control and AGE‐treated diabetic. A normal, saline‐treated, control group was also included. STZ‐induced diabetic rats lost significant weight during the experiment with AGE‐treated rats maintaining their initial weights. Blood glucose as well as serum cholesterol and triglycerides were significantly elevated in diabetic rats, and significantly lowered by AGE treatment. Serum insulin level was decreased nearly 30‐fold in diabetic rats and was increased significantly by AGE treatment; while serum fructosamine was increased about 2.5 fold in diabetic rats with a marked decrease in AGE‐treated diabetic rats. Significant decreases in total antioxidant levels (26‐39%) and catalase activity (50‐71%) were observed in serum, kidneys and livers of diabetic rats with significant recovery in AGE‐treated animals. In contrast, lipid peroxidation (MDA levels) increased in kidneys (57%) and livers (44%) of diabetic rats and was significantly lowered in AGE‐treated diabetic rats. Protein levels in serum, liver and kidneys were significantly lowered in diabetic rats with increased levels in AGE‐treated rats. Thus, oral AGE treatment was effective in ameliorating oxidative stress and other indicators of diabetes in STZ‐induced diabetic rats. The study was supported by KU grant #SL 06/13.
Oxyresveratrol Normalized Body Weight Gain and Feed Efficiency of Mice Fed High‐Fat Diet
Authors: Li Edmund , Tan Hui , Wang Ming
Published: June 2021

Many polyphenols can impact the biological system. For example, stilbenoid such as resveratrol has been extensively studied and known to improve metabolic health. Through its influences on Sirtuin 1, resveratrol slows aging and attenuates a number of metabolic derangements. Despite sharing similar structure, relatively little is known about oxyresveratrol (OXY). There is evidence that OXY possesses anti‐inflammatory as well as anti‐oxidative properties. We recently demonstrated OXY, at doses that did not induce cytotoxicity, to possess anti‐adipogenic action in 3T3‐L1 cells by inhibiting differentiation through inducing cell cycle arrest. In the present study, the effect of OXY supplementation on high‐fat diet fed mice was examined. C57bl/6 mice were randomly assigned to control (5% fat by weight, LF), high‐fat (30%, HF) and high‐fat supplemented with 0.25% and 0.5% OXY (OXY1 and OXY2, respectively) diet group. At week 5, LF (28.0 g) and OXY1 (27.8 g) mice had similar body weight that were lower than HF (34.1 g) mice but higher than OXY2 (25.6 g) mice (p < 0.05). Cumulated energy intakes of OXY1 (2.19 MJ) and OXY2 (2.13 MJ) mice was similar and significantly lower than that of HF (2.42 MJ) mice (p < 0.05) but intake of OXY1 mice was not different from LF mice (2.27 MJ). Feed efficiency (body weight gain/ energy intake) was highest in HF (5.91) mice and progressively decreased with OXY2 mice exhibiting significantly lower value (2.83) than the OXY1 (3.73) and LF (3.69) mice (p < 0.05). Thus, the addition of 0.25% OXY to a HF diet resulted in mice with energy intake, body weight gain and feed efficiency matched with LF mice. Hence oxyresveratrol and resveratrol may share similar health benefits through influencing cellular energy metabolism and cell cycle activity. (Supported by a HKU grant)
Elevated Umbilical Cord Cytokines are Related to Birth Size in HIV‐exposed and Unexposed Infants
Authors: Wilkinson Amanda , Pedersen Sarah , Urassa Mark , Michael Denna , Andreasen Aura , Todd Jim , Kinung'hi Safari , Changalucha John , McDermid Joann
Published: June 2021

Background

Infection causes immune activation and inflammatory cytokines may be mediators of intrauterine growth restriction (IUGR). While infection and IUGR are common in developing regions, the intrauterine cytokine environment and its impact on birth size is undefined. Understanding the fetal environment mediated by multiple cytokines may inform interventions targeting birth anthropometry.

Objective

To investigate the relationship between umbilical cord cytokines and birth size.

Methods

Umbilical cord cytokines (IFN‐γ, IL‐1β, IL‐2, IL‐6, TNF‐α, IL‐12p70, IL‐10, IL‐13) were multiplexed from 50 singleton deliveries of women residing in rural Tanzania (38% HIV‐positive). Birth weight and length were assessed using linear regression models adjusted for maternal age, nutritional status, HIV, and infant gender.

Results

Cord IFN‐γ, IL‐1β, TNF‐α, IL‐12p70, and IL‐10 were each associated with reduced birth weight (grams; ‐532, P<0.01; ‐372, P=0.04; ‐315, P=0.03; ‐721, P<0.01; ‐278, P=0.04; respectively) and IFN‐γ, TNF‐α, and IL‐12p70 with reduced length.

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Cord cytokines were not associated with gestational age at delivery and did not differ based on maternal HIV status.

Conclusions

Elevated cord blood cytokines, which suggest intrauterine immune activation and inflammation, were associated with clinically important reductions in birth weight and length. Understanding these relationships may be key to optimizing fetal growth outcomes in this setting.
Fatty Acid Desaturase Single Nucleotide Polymorphisms Modify the Effect of Prenatal Supplementation with Docosahexaenoic Acid on Birth Weight
Authors: Gonzalez‐Casanova Ines , Rzehak Peter , Hao Wei , Aryeh Stein , Barraza‐Villarreal Albino , Garcia‐Feregrino Raquel , Rivera Juan , Romieu Isabelle , Villalpando Salvador , Koletzko Berthold , Ramakrishnan Usha
Published: June 2021

Maternal single nucleotide polymorphisms (SNP) in the Fatty Acid Desaturase genes (FADS) modulate the conversion of biologically inactive dietary polyunsaturated fatty acids (PUFA) into arachidonic and docosahexaenoic (DHA) acid, which are essential for fetal development. We assessed if four FADS SNPs (rs174445, rs174556, rs174602, rs498793) modified the association of prenatal DHA supplementation with birth weight (BW). 1,094 pregnant women in Cuernavaca, Mexico were randomized to supplementation with 400 mg/day of DHA or a placebo from 18‐22 w of gestation through delivery. We included 677 live births with maternal genotype information available (65% of the original sample). Mean (±SD) BW was 3,210 g (±466) and BW for gestational age z‐scores (WAZ) relative to the WHO Growth Standards was ‐0.24 (±1.00). There were no intent‐to‐treat differences in birth weight. We found a significant interaction by SNP rs174602 (p=0.02), where offspring of carriers of alleles TT and TC in the intervention group were heavier than those in the placebo (WAZ = ‐0.14±0.14 and ‐0.18±0.07 vs.‐0.55±0.14 and ‐0.40±0.8, respectively); while the opposite was observed among the offspring of rs174602 CC homozygotes (WAZ= ‐0.23±0.09 intervention vs. ‐0.02 ±0.08 placebo). We found no significant effect modification by the other three FADS SNPs. Differential responses to prenatal DHA supplementation trials based on target populations' genetic makeup and PUFA dietary intake could explain the mixed evidence of the impact of DHA on BW. Funded by NIH and the Nutricia Research Foundation.
Prevalence of Inflammation Varies among Preschool Aged Children across 12 Countries
Authors: Merrill Rebecca , Sullivan K , Northrop‐Clewes C , Flores‐Ayala R , Namaste S , Serdula M , Suchdev P
Published: June 2021

Inflammation is known to affect many biomarkers used in the assessment of micronutrient status. The prevalence of inflammation as measured by C‐reactive protein (CRP, >5 mg/L) and alpha1‐acid glycoprotein (AGP, >1 mg/L) and individual‐level factors associated with these markers have not been characterized across a variety of environments. Using data from 12 Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia (BRINDA) household‐based survey datasets, survey design‐adjusted prevalence estimates of inflammation among preschool children were calculated. Prevalence estimates were compared overall and by sex, age (6‐11mo, 12‐23, 24‐35, 36‐59, association measure if >2 groups included), socioeconomic status (SES, asset index quintile), stunting (<‐2 height‐for‐age z score) and wasting (<‐2 weight‐for‐height z score) (chi square, p<0.05). Prevalence of elevated CRP and AGP ranged from 6.0 (USA) to 40.2% (Cote D'Ivoire) and 20.8 (Philippines) to 64.3% (Cote D'Ivoire), respectively. Sex was associated with inflammation in Laos. Age was inconsistently not (n=5), negatively (n=3, with AGP only), and positively (n=2) associated with inflammation. Inflammation was inversely associated with SES in 6 of 8 countries with relevant data. In a majority of countries AGP was positively associated with stunting (n=7) and wasting (n=5). While there is a strong negative association across countries between inflammation and both growth and SES in preschool children, age and sex showed inconsistent relationships. There is a need to better understand factors influencing the risk of inflammation in various settings.
Intake of Soy Isoflavones Reduces Breast Cancer Incidence among Women in North America
Authors: Jaceldo‐Siegl Karen , Gatto Nicole , Beeson Lawrence , Fraser Gary
Published: June 2021

Inconsistency in findings from studies on soy intake and breast cancer risk, particularly among Western populations, has given greater weight to concerns about the safety of soy consumption. We prospectively examined associations between soy consumption and breast cancer incidence by Cox proportional hazards regression, controlling for important confounders. Of 62,511 Seventh‐day Adventist women recruited, 50,288 participants remained after exclusions. Soy consumption was assessed at baseline by a quantitative FFQ. New breast cancer cases through 2011 were identified by record linkage with data from 48 state cancer registries. There were 892 new breast cancer cases during a mean follow‐up of 7.87 years. Intake of soy protein, soy isoflavones, soybeans and tofu, soymilk, and meat analogues were lower among women with breast cancer than those without cancer. Subjects in the highest soy protein intake quintile (median of 18.24 g/d) compared the lowest quintile (median of 0.13 g/d) had a 21% reduced risk of developing breast cancer (RR = 0.79, 95% CI = 0.64, 0.97; p for trend = 0.03). Women in the highest quintile of total isoflavones intake (median of 44.4 mg/d) had a 22% reduced risk of breast cancer compared to those with a median intake of 1.15 mg/d (RR = 0.78, 95% CI = 0.63, 0.97; p for trend = 0.01). For soybeans and tofu, soy milk and meat analogues, there was a suggestion that greater intake compared to the lowest quintile of intake could be protective, but the effect sizes were smaller as these represented only portions of the total soy intake. In conclusion, soy intake is associated with reduced risk of breast cancer in a largely Caucasian and African‐American population from North America.
Interactions between calcium intake and polymorphisms in genes essential for calcium reabsorption and risk of colorectal neoplasia in a two‐phase study
Authors: Zhao Jing , Shrubsole Martha , Ness Reid , Zhu Xiangzhu , Hibler Elizabeth , Cai Qiuyin , Long Jirong , Jiang Ming , Kabagambe Edmond , Zhang Bing , Hou Lifang , Smalley Walter , Edwards Todd , Giovannucci Edward , Zheng Wei , Dai Qi
Published: June 2021

Background

Calcium homeostasis plays a key role in cell proliferation and apoptosis. We hypothesized that polymorphisms in the SLC8A1 and other four calcium‐regulating genes interact with calcium intake in relation to the risk of colorectal neoplasia.

Design

A two‐phase (discovery and replication) study was conducted within the Tennessee Colorectal Polyp Study, including a total of 1275 cases and 2811 controls.

Results

In this two phase study, the interaction between rs4952490 (SLC8A1) and calcium intake in relation to adenoma risk was identified and replicated. We found an inverse association between calcium intake (1000‐2000 mg/day) and colorectal adenomas, particularly for multiple/advanced adenomas, among the G‐allele carriers but not among homozygous carriers of the common variant (A) in rs4952490. In the joint analysis of SLC8A1, KCNJ1and SLC12A1SNPs, carriers of variant alleles in at least two genes and with calcium intake above the DRI (1000 mg/day) were approximately 40‐60% less likely to have adenomas than those whose calcium intake was below the DRI. The association was stronger for multiple/advanced adenomas. No association was found among those who did not carry any variant alleles in these genes.

Conclusions

These findings, if confirmed, may provide a new avenue for the personalized prevention of colorectal adenoma and cancer.
Global Genomic Analysis Reveals Regeneration Associated Signaling Network After Acetaminophen Overdose
Authors: Bhushan Bharat , Borude Prachi , Gunewardena Sumedha , Apte Udayan
Published: June 2021

Liver regeneration is critical determinant of survival following acetaminophen (APAP) overdose, but the mechanism of this regenerative response remain unclear. We developed an incremental dose model consisting of “regenerative” dose (300 mg/kg) and a “non‐regenerative” dose (600 mg/kg) of APAP in mice to study mechanisms of regeneration after APAP overdose. Here we compared microarray‐based IPA‐assisted global gene expression patterns after 300 or 600 mg/kg APAP treatment in mice. Analysis of unique genes revealed activation of cell cycle inducers specifically in APAP300 group while induction of cell cycle repressors specifically at APAP600. IPA analysis revealed that DNA replication and repair pathways were specifically altered only at APAP300. Upstream regulators analysis predicted that APAP300 treatment resulted in activation of Myc, FoxM1, HIF1α and β‐catenin target genes and inhibited HNF4α and TRIM24 regulated genes. Treatment of APAP600 dose resulted in activation of p53 and NFκB‐inhibitor A and inhibition of β‐catenin and C/EBPα target genes. Predicted role of β‐catenin and NFκB in regeneration is consistent with our confirmatory studies using ChIP and overexpression analysis in mice. In conclusion, our genome wide analysis identified dose dependent signaling interactions modulating liver regeneration after APAP overdose, which is useful tool to identifying novel therapeutic targets and building new computational models of liver regeneration.
Wnt/Beta‐Catenin Cooperates With Yap Signaling To Promote Hepatobiliary Repair In A Model Of Chronic Liver Injury
Authors: Nejak‐Bowen Kari , Okabe Hirohisa , Monga Satdarshan
Published: June 2021

Proliferation of atypical ductules and compensatory hepatocyte transdifferentiation to cholangiocytes is a hallmark of 3,5‐diethoxycarbonyl‐ 1, 4‐dihydro‐collidine (DDC) diet‐induced injury in mice. Because liver‐specific beta‐catenin conditional KO mice exhibit fewer proliferating ductules after DDC, we hypothesized that Wnt signaling plays a role in this process. To test this, WT animals on control and DDC diet were analyzed for Wnt expression. We found upregulation of 3 Wnts – 7a, 7b, and 10a – in the portal triad of DDC‐fed mice, as determined by tissue microdissection. Cell sorting showed expression of these three Wnts exclusively in the EpCAM+ cell compartment. Addition of Wnt7b and 10a to small cholangiocyte cell line induced proliferation in an autocrine manner, consistent with an increase in CK19+/Ki67+ cells after DDC. In contrast, direct co‐culture of Hek293 cells expressing recombinant Wnt7a significantly increased Sox‐9 gene expression in AML12 cells and primary hepatocytes. To elucidate the role of beta‐catenin in transdifferentiation, we analyzed liver‐specific transgenic (TG) ser45‐mutant b‐catenin‐expressing mice after DDC diet. Compared to WT, TG had significantly upregulated expression of EpCAM and CK19, and more Sox‐9+ hepatocytes. Further, Yap, which regulates liver cell fate, is increased in TG hepatocyte nuclei, concomitant with increased expression of Yap target genes. Thus, Wnt/beta‐catenin signaling cooperates with Yap pathway to regulate hepatobiliary repair after DDC injury.
Liver Regeneration Deficit in Mice Following EGFR and Met Elimination
Authors: PARANJPE SHIRISH , Bowen William , Haynes Meagan , Mars Wendy , Orr Anne , Paranjpe Tejas , Luo Jianhua , Michalopoulos Amantha , Michalopoulos George
Published: June 2021

Acute loss of liver mass following toxic or surgical means elicits hepatic regeneration and restoration of liver tissue to its original mass, indicating a tightly regulated growth process. A two‐thirds partial hepatectomy (PHx) in mice and rats results in rapid induction of more than 100 genes, (that are not expressed in resting liver) & activation of multiple signaling pathways. EGFR & MET, the two major mitogenic receptor tyrosine kinases, are activated within 15 ‐ 30 minutes following a PHx. The MET‐EGFR signaling pathway plays a significant role in is activated within 15‐30 minute following a PHx in mice and rats. The role played by these two pathways during liver regeneration was investigated by utilizing mice that had c‐met deleted in the liver using a tamoxiphen inducible Cre‐loxP system. Following deletion of c‐met, mice were administered (80mg/kg, i.p) of Canertinib, a pan EGFR inhibitor. Mice were injected a day before PHx and then everyday for seven days. A partial hepatectomy was carried out two hours later. Appropriate vehicle controls were also used. In mice treated with Tyrosine kinase inhibitors, pEGFR levels were significantly reduced compared to vehicle treated controls. A significant reduction in Ki67 labeling was also evident, as was a reduction in liver to body wight ratio, suggesting a liver regeneration deficit. Microarray analyses of inhibitor and vehicle treated controls indicated significant down regulation of cell cycle related genes, that was confirmed by western blot analyses. There appears to be no redundancy and compensatory scheme for liver regeneration when both Met and EGFR are blocked.
Blockade of Tim‐4 Aggravates Atherosclerosis
Authors: Foks Amanda , Engelbertsen Daniel , Alberts‐Grill Noah , Kuperwaser Felicia , DeKruyff Rosemarie , Freeman Gordon , Lichtman Andrew
Published: June 2021

Introduction

Proteins of the transmembrane T cell immunoglobulin and mucin domain (Tim) family are expressed by numerous immune cells, recognize phosphatidylserine (PS) exposing cells and exert either a costimulatory or coinhibitory role. Tim‐4, present on macrophages and antigen‐presenting cells, has been shown to play a critical role in the clearance of apoptotic cells, regulates the number of PS‐expressing activated T cells, and is genetically associated with triglyceride levels. Since both apoptosis and the presence of activated T cells contribute to atherosclerotic lesion formation, we investigated whether interference in Tim‐4 function would affect atherosclerosis.

Methods and Results

LDLr‐/‐ mice were fed a Western‐type diet for 4 weeks while being treated twice a week i.p. with an anti‐Tim‐4 (21H12) mAb that blocks PS recognition and phagocytosis or an isotype control (rat IgG1). Treatment with anti‐Tim‐4 increased the area of atherosclerotic lesion in the aortic root by 52% (8.58±1.40%) compared with control mice (5.69±0.51%, P<0.01), independent of plasma cholesterol and triglyceride levels. Anti‐Tim‐4‐treated mice showed increased activated T cell numbers and ‘late’ apoptotic cells in the circulation. Additionally, anti‐Tim‐4 treatment induced splenomegaly, enhanced splenocyte proliferation and increased IFNγ+ (Th1) and IL‐4+ (Th2) cells.

Conclusion

Blockade of Tim‐4 aggravates atherosclerosis likely by prevention of phagocytosis of PS‐expressing apoptotic cells and activated T cells by Tim‐4‐expressing cells.
KRIT1 Depletion Modifies Endothelial Cell Behavior Through Increased VEGF Signaling
Authors: DiStefano Peter , Kuebel Julia , Sarelius Ingrid , Glading Angela
Published: June 2021

Disruption of endothelial cell‐cell contact is a key event in many cardiovascular diseases, and a characteristic of pathologically activated vascular endothelium. The CCM family of proteins (KRIT1, PDCD10, and CCM2) are critical regulators of endothelial cell‐cell contact and vascular homeostasis. Here, we show novel regulation of vascular endothelial growth factor (VEGF) signaling in KRIT1‐depleted endothelial cells. Loss of KRIT1 and PDCD10, but not CCM2, increases nuclear β‐catenin signaling and up‐regulates VEGF‐A protein expression. In KRIT1‐depleted cells, increased VEGF‐A levels led to increased VEGFR2 activation and subsequent alteration of cytoskeletal organization, migration, and barrier function, and to in vivo endothelial permeability in KRIT1 deficient animals. VEGFR2 activation also increases β‐catenin phosphorylation, but is only partially responsible for KRIT1 depletion‐dependent disruption of cell‐cell contacts. Thus, VEGF signaling contributes to modifying endothelial function in KRIT1 deficient cells and microvessel permeability in Krit1+/‐mice, however VEGF signaling is not the primary cause of disrupted endothelial cell‐cell contacts in the absence of KRIT1.

Sources of Funding:

AHA 14PRE20380009 to Peter DiStefano

NIH HL117885‐01 to Angela Glading
Vascular Smooth Muscle Sirtuin‐1 Protects Against Aortic Dissection During Angiotensin II Infusion
Authors: Fry Jessica , Shiraishi Yasunaga , Gao Yuan , Weisbrod Robert , Maziuk Brandon , Weng Xiang , Morgan Kathleen , Cohen Richard , Seta Francesca
Published: June 2021

BACKGROUND

Sirtuin‐1 (SIRT1), an NAD+‐dependent deacetylase, is a key enzyme in the cellular response to metabolic, inflammatory, and oxidative stresses, however the role of SIRT1 in vascular smooth muscle (VSM) is unclear.

OBJECTIVE

To study the role of VSM SIRT1 in the physiological response of the aortic wall to angiotensin (Ang) II, a potent oxidant and inflammatory stimulus.

METHODS

We generated a VSM cell specific SIRT1 knock out mouse (SMKO) and infused AngII (1 mg/kg/d) by osmotic minipump and evaluated endpoints after 14 days.

RESULTS

SMKO mice had a drastically high mortality (70%) caused by aortic dissection, at both thoracic and abdominal sites, as early as 6 days after infusion of AngII, but not after equi‐pressor norepinephrine (10 mg/kg/d). Aortas from AngII‐treated SMKO mice had severely fragmented and disorganized elastic lamellae with frequent elastin breaks compared to WT/AngII and increased aortic stiffness measured ex vivo. Metalloproteinase (MMP)‐2 expression was increased in the aortas of both saline‐ and AngII‐treated SMKO mice compared to WT littermates. In gel zymography on whole aortic homogenates confirmed increased MMP activity in SMKO. Similarly, VSM cells isolated from SMKO aortas exhibited increased expression of MMP2, indicating a VSM rather than myeloid source.

CONCLUSIONS

The high incidence of aortic dissection in AngII‐treated SIRT1 SMKO mice (80%) indicate that endogenous SIRT1 in aortic smooth muscle is required to maintain the structural integrity of the aortic wall in response to oxidant and inflammatory stimuli. The SMKO infused with AngII is a novel model of aortic dissection. Research Support: NHLBI grant HL105287
CRISPLD2 in Hepatic Fibrogenesis and Cholangiocellular Carcinoma Progression
Authors: Saravanan Chandrassegar , Spence Cheryl , Trevaskis James , Wang Xiaosong , Galarneau Jean‐Rene , Chutkow William , Mansfield Keith
Published: June 2021

Studies in the past have shown that bile ductular hyperplasia correlates with the degree of hepatic fibrosis and that myofibroblasts are a major component of cholangiocellular carcinoma (CCA). However, the mechanism of cross‐talk between bile ductular epithelial cells and hepatic stellate cells during hepatic fibrogenesis and CCA progression was not established. In this study, we identified CRISPLD2, a secretory protein reported to be critical for epithelial morphogenesis during lung and kidney development, as one of the top differentially up‐regulated genes in the liver of a mouse model of nonalcoholic steatohepatitis (NASH). A combined in situ hybridization, histochemistry, immunohistochemistry and image analysis suggested that CRISPLD2 mRNA was expressed in hepatic stellate cells accompanying bile ductules and collagen fibers in the liver of mouse model of NASH and human cirrhotic liver. Furthermore, cancer‐associated myofibroblasts express CRISPLD2 mRNA in human cholangiocarcinoma tissues. These data suggest that CRISPLD2 may play a role in the branching morphogenesis of biliary epithelial cells and participate in hepatic fibrogenesis and cholangiocellular carcinoma progression. Further characterization of the role of CRISPLD2 is important as it may serve a novel candidate for targeted therapy and/or biomarker for hepatic fibrosis and CCA.
EM of Pathogen Secretion Systems: Unfolded Protein Transport across Membranes in Action
Authors: Marlovits Thomas
Published: June 2021

We are focusing on two fundamental aspects in biology (1) assembly of multicomponent systems into functional nanomachines and (2) transport of proteins across membranes. Both are found in type three secretion systems (T3SS), which are required of bacterial secretion of proteins into the host that subvert the host antibacterial response in order to promote infection. These systems utilize a 3.5 MDa syringe‐like, membrane embedded “injectisome” containing an ~800 Å long needle complex thought to cross multiple membranes to connect the intracellular compartments of the bacteria and the host. The striking resemblance of the injectisome to a bona fide syringe, revealed by electron microscopy has led to the hypothesis that bacterial proteins are secreted through the needle complex into the host. I will discuss how and where substrates are passed through the T3SS and across two membranes by visualizing injectisomes in action and in situ.