bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary phytosterols intakes are inversely associated with colorectal cancer risk among Chinese population
Authors: Zhang Cai‐Xia , Huang Jing , Xu Ming , Luo Wei‐Ping , Fang Yu‐Jing
Published: November 2023

Objective

According to the previous studies based on rodent models, phytosterols provided protection against colon carcinogenesis probably by inhibiting dysregulated cell cycle progression and inducing apoptosis. However, epidemiological studies on the relationship between phytosterols and colorectal cancer risk were quite limited. The aim of this study was to investigate the association between dietary phytosterols intakes and colorectal cancer risk among Chinese population.

Methods

A case‐control study of 1363 consecutively recruited colorectal cancer cases and 1363 frequency‐matched controls (age and sex) was conducted from July 2010 to May 2015 in Guangzhou, China. Dietary information was collected by using a validated interviewer‐administered food frequency questionnaire. Five subclasses of phytosterols (β‐sitosterol, campesterol, β‐sitostanol, campestanol and stigmasterol) were obtained from food content according to the Chinese Food Composition Table. The odds ratios (ORs) and 95% confidence intervals (95% CIs) of colorectal cancer risk were assessed by multivariate logistic regression models after adjusting for various potential confounders.

Results

An inverse association was found between the consumption of β‐sitosterol, campesterol, β‐sitostanol, campestanol and total sterols and colorectal cancer risk. After adjusting various confounders, ORs of the highest quartile compared with the lowest quartile intake were 0.44 (95% CIs 0.35–0.56, Ptrend < 0.01) for β‐sitosterol, 0.56 (95% CIs 0.45–0.71, Ptrend < 0.01) for campesterol, 0.58 (95% CIs 0.46–0.73, Ptrend < 0.01) for β‐sitostanol, 0.60 (95% CIs 0.48–0.76, Ptrend < 0.01) for campestanol and 0.50 (95% CIs 0.40–0.63, Ptrend < 0.01) for total sterols, respectively. No significant association was observed between stigmasterol intake and colorectal cancer risk. Subgroup analysis by cancer site showed that the inverse associations between β‐sitosterol, campesterol, β‐sitostanol and campestanol and total sterols intakes and colorectal cancer risk were observed in both colon and rectal cancer sites. Stratified analysis by sex showed that dietary intakes of β‐sitosterol, campesterol, stigmasterol, β‐sitostanol, campestanol and total sterols were inversely associated with colorectal cancer risk among men. There was no significant inverse association between consumption of any of the phytosterols and colorectal cancer risk among women. However, stigmasterol intake was positively associated with colorectal cancer risk among women.

Conclusion

Consumption of β‐sitosterol, campesterol, stigmasterol β‐sitostanol and campestanol was inversely associated with colorectal cancer risk. No significant association was observed between stigmasterol intake and colorectal cancer risk.

Support or Funding Information

This study was supported by Guangdong Natural Science Foundation (No: 2014A030313188).
Black Berry Polyphenol Reduce Nox1 Function to Inhibit Senescence in Vascular Smooth Muscle Cells
Authors: Huang Jingwen , Feresin Rafaela , Zhao Yitong , Pourafshar Shirin , Arjmandi Bahram H. , Salazar Gloria
Published: November 2023

Introduction

The consumption of fruits and vegetables has been shown to decrease cardiovascular diseases (CVD) incidence mainly due to the polyphenol content in these foods. Angiotensin II (Ang II) plays an important role in inducing ageing‐related diseases including CVD as it increases the production of reactive oxygen species (ROS) and reduces cellular antioxidant capacity leading to vascular senescence. The NADPH oxidase Nox1 generates superoxide and is involved in Ang II‐induced pathological effects.

Objectives

The purpose of this study was to investigate the role of blackberry (BL) polyphenol extracts in Ang II‐induced senescence in vascular smooth muscle cells (VSMCs) and the possible molecular mechanism involved.

Methodology

VSMCs treated with purified BL polyphenol extracts (200 μg/ml) were incubated with or without Ang II (100 nM). After three days of treatment, cells were analyzed for 1) senescence, measured by senescence associated β‐galactosidase (SA‐β‐gal) activity; 2) western blot to determine the activation of Ang II signaling and the expression of the senescence markers, p21 and p53, as well as antioxidant enzymes; and 3) ROS levels assessed by 2′,7′‐dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescence.

Results

We found that BL polyphenol extracts prevented Ang II‐induced signaling, increased superoxide dismutase (SOD) 1 expression and reduced ROS levels preventing senescence in VSMCs. These effects were associated with down‐regulation of Nox1 expression. Further, BL prevented senescence induced by Nox1 over‐expression.

Conclusions

The protective role of BL polyphenols in preventing senescence is mediated by down‐regulation of Nox1. Thus, the consumption of BL could be effective in reducing the burden of CVD.
Food Label Use Improves Dietary Quality and Mediates Improved Glycemic Control in Latinos with Type 2 Diabetes: The DIALBEST trial
Authors: SAMUEL GRACE KOLLANNOOR , Shebl Fatma M , Segura‐Pérez Sofia , Chhabra Jyoti , Vega‐López Sonia , Pérez‐Escamilla Rafael
Published: November 2023

Background

Culturally‐ and health literacy‐appropriate education has proven benefits in type 2 diabetes management among Latinos who disproportionately suffer from the disease and related complications. There is limited empirical evidence documenting the effect of diabetes‐specific education on food label (FL) use. Similarly, little is known about the effect of FL use on glycemic control among individuals with T2D.

Objectives

To determine the impact of a community health worker (CHW)‐led intervention on FL use, and if FL use and diet mediate the intervention's impact on blood glucose control.

Methods

Latinos (N=203; intervention=100; control=103) with type 2 diabetes were enrolled in a randomized control trial and assessed at baseline, 3, 6, 12 and 18 months. Intervention included 17 home‐based sessions over a 12‐month period from CHWs in addition to the ‘standard of care’ available to all. Data on FL use, dietary quality (Healthy Eating Index‐2010 assessed from one 24hr recall), covariates, and glycemic control (glycated hemoglobin (HbA1c)) were collected at baseline, 3, 6, 12 and 18 months. Data were analyzed using mixed effects and multi‐level structural equation modelling.

Results

FL use among the intervention group (vs. control) was significantly higher at 3, 12, and 18m; Overall repeated measures analyses suggests higher odds of FL use among the intervention participants compared to the controls [OR=2.99 (95% CI: 1.69, 5.29)]. FL use and dietary quality mediated improved HbA1c levels [intervention vs. controls: −0.09% (−0.23, −0.02)].

Conclusions

Culturally tailored CHWs‐led intervention increased FL use. FL use and better dietary quality mediated the HbA1c intervention effect among Latinos with type 2 diabetes.

Support or Funding Information

This study was funded by the Connecticut NIH Export Center for Eliminating Health Disparities among Latinos (NIH‐ NCMHD grant # P20MD001765 to Rafael Pérez‐Escamilla).
Menaquinone‐7 Supplementation Improves Lipid Profile in Obese African‐American Children: A Randomized Controlled Trial
Authors: Pollock Norman K , Nguyen Joshua , Fain Mary Ellen , Gower Barbara A. , Bassali Reda , Davis Catherine L
Published: November 2023

The childhood obesity surge has led to a larger population of children with dyslipidemia. Without intervention, dyslipidemia is likely to become atherosclerotic cardiovascular disease in adulthood. Menaquinones, also known as vitamin K2, have been recently focused as a pivotal nutrient in improvement in lipid related parameters, possibly via increased carboxylation of matrix Gla‐protein (MGP). Therefore, this study investigated the dose‐response effect of menaquinone‐7 (MK‐7) supplementation on lipid profile and the inactive form of MGP (dephospho‐uncarboxylated MGP, dp‐ucMGP) in obese African‐American (AA) children. Associations between the changes in dp‐ucMGP and the changes in lipid related parameters were also determined. Fifteen obese AA children (mean age, 12.3 ± 2.9 years; mean BMI percentile, 98.8 ± 1.0; 60% female) were randomly allocated to either the control group receiving placebo or the low‐dose (45‐μg/d) or high‐dose group (90‐μg/d) receiving MK‐7 supplementation for 8 weeks. At baseline and posttest, fasting blood samples were collected for assessment of serum levels of triglycerides, total cholesterol, HDL‐cholesterol, non‐HDL‐cholesterol and LDL‐cholesterol, and plasma levels of dp‐ucMGP. After 8 weeks, dp‐ucMGP decreased significantly and dose‐dependently in the 45‐μg and 90‐μg MK‐7 supplementation groups by 8% and 22%, respectively (P=0.02). A dose‐response benefit of MK‐7 supplementation was also observed for triglycerides, total cholesterol, non‐HDL‐cholesterol, and LDL‐cholesterol as indicated by significant downward trends (all P < 0.05). There was no dose‐response effect of MK‐7 on HDL‐cholesterol. Pearson's bivariate analyses revealed that changes in triglycerides (r = 0.69) and non‐HDL cholesterol (r = 0.65) were associated with changes in dp‐ucMGP (both P < 0.04). After 8‐weeks, MK‐7 supplementation demonstrated dose‐response benefits on lipid profile in obese children. Our study provides the rationale that larger intervention trials are needed to determine whether vitamin K2 supplementation slows atherosclerosis development by increasing MGP carboxylation.

Support or Funding Information

This work was funded by Georgia Regents University's Intramural Grants Program.
Dietary Intake Assessment of Snacking among Children in China and U.S.
Authors: Wang Dantong , Eldridge Alison L
Published: November 2023

Introduction

Snacking between meals is growing in importance as an eating occasion in children across the world, but there are increasing concerns about the types of foods and their nutritional quality as well as the amount of energy snacking provides. Diet, including snacking, is highly influenced by culture; however few studies have explored snacking habits across cultures.

Objective

To compare snacking prevalence, energy contribution and major food sources of energy from snacks between children in China and the U.S. to understand the impact of culture on snacking habits.

Methods

Data from the China Health and Nutrition Survey 2011 and the U.S. National Health and Nutrition Examination Survey 2009–12 were used. The USDA What We Eat in America food grouping system was applied to classify food groups. Snacking was self‐defined by study participants in both countries. All foods and drinks reported as snacks by the participants were aggregated into Morning (0:00–12:00), Afternoon (12:00–18:00) and Evening (18:00–24:00) “snacking periods.” Per capita weighted average (U.S.) and 3‐d average (China) intakes of the amounts of foods and beverages consumed during different snacking periods were calculated. In total, 1326 Chinese and 3647 U.S. children ages 4 to 13 years were included.

Results

Almost all U.S. children reported snacking (95.7%), much higher than that of Chinese children (69.3%, p<0.05). However among the three snacking periods, the afternoon period was the most commonly reported snacking period in both countries, followed by the evening period. The energy contribution of total snacking was 482 kcal in U.S. children, corresponding to 25% of their daily energy intake. In Chinese children, total snacking provided on average 138 kcal, which was only 10% of their daily energy intake. The top 3 food sources of energy during snacking were Snacks and Sweets, Non‐alcoholic Beverages, and Milk and Dairy in U.S. children, and Snacks and Sweets, Fruits, and Milk and Dairy in Chinese children. However, the most frequently reported snacks were Fruits in China (56.1%), and Snacks and Sweets in U.S. (76.5%).

Discussion

Snacking habits are different between children in U.S. and China, both in terms of frequency and specific foods consumed. Snacking plays an important role in nutrient and energy intakes in both Chinese and U.S. children, though energy contribution and nutritional impact from snacks was very different between the countries. Nutrition education and intervention programs on snacking need to be culturally specific.

Support or Funding Information

Funded by Nestlé Research Center, Lausanne, Switzerland.
Has the Sodium Content of US Households’ Packaged Food and Beverage Purchases Improved in the Past 15 Years?
Authors: Poti Jennifer M , Dunford Elizabeth , Popkin Barry M
Published: November 2023

Background

Despite recent US initiatives to reduce the sodium content of packaged foods, corresponding changes in the sodium content of households’ food and beverage purchases have not been evaluated.

Objectives

Our objectives were to evaluate 15‐year trends in the amount of sodium (mg/d per person) in US households’ store‐bought consumer packaged goods (CPGs) purchases, top sources of sodium for household purchases, and the sodium content of food purchases.

Methods

We analyzed data from the 2000–2013 Homescan panel, a nationwide longitudinal study of US households (n=164,084; 706,970 year‐level observations) that record all CPG foods and beverages purchased from retail food stores throughout the year. Barcodes were linked to corresponding Nutrition Facts Panels for over 1.2 million unique barcoded products, in order to utilize time‐varying brand and product‐specific nutrition information. Multivariable‐adjusted longitudinal linear and logistic random effects models were used to examine sodium trends while controlling for changes in the distribution of sociodemographic factors in the US.

Results

Adjusted mean total sodium in households’ grocery store purchases significantly decreased from 2351 to 1992 mg/d per person between 2000 and 2013 (β = −358 mg/d, 95% CI: −373, −344), with significant declines beginning in 2006. Many of the top sources of sodium in households’ CPG purchases contributed to this decline, notably breads (−63 mg/d), condiments and sauces (−58 mg/d), and salty snacks (−46 mg/d). However, the contribution from other top sources, such as prepared meals/mixed dishes (204 mg/d), processed meat (129 mg/d), and cheese (110 mg/d), increased or experienced little change (<10mg/d). The overall sodium content of packaged food purchases significantly declined from 471 mg/100g in 2000 to 416 mg/100g in 2013 (β = −55 mg/100g, 95% CI: −57, −53). Nonetheless, in all years between 2000–2013, >97% of US households had total food and beverage CPG purchases that exceeded the Dietary Guidelines for Americans upper limit of 2300 mg sodium per 2000 kcal.

Conclusions

Despite improvements in the past 15 years, the sodium content of the CPG products that Americans purchase remains high. The majority of US households have CPG food and beverage purchases that do not meet sodium recommendations. Our findings can help identify areas where future reformulations and efforts to shift consumer product selection can have the greatest impact. Ongoing monitoring of household purchases is needed to evaluate sodium reduction initiatives in the US.

Support or Funding Information

Funding for this study comes from the Robert Wood Johnson Foundation (Grants 67506, 68793, 70017, 71837), NIH (R01DK098072), and the CPC 5 R24 HD050924.
Socioeconomic Disparities in Dietary Intake and Food Purchasing of Foods and Beverages of Varying Healthfulness in Mexico
Authors: Lopez‐Olmedo Nancy , Taillie Lindsey P Smith , Popkin Barry M
Published: November 2023

The aim of this study was to compare the energy intake and purchasing of healthy and less healthy foods and beverages by socioeconomic status in a nationally representative sample of Mexicans. A 24‐hour recall from the Mexican National Health and Nutrition Survey (ENSANUT) 2012 is compared with a representative sample of Food Purchasing Database (FPD) from Nielsen Co. Food and beverages categories from both data sets were groups according to Mexico's taxation categories for beverages and foods. Socioeconomic status (SES) indices for each dataset, based primarily on education and household assets, were used and SES was further classified by tertiles. Linear regression models were conducted to predict means with their respective standard errors of energy intake and volume purchased per capita per day for each of the four food groups (less healthy and healthy food and beverages) by SES and adjusting for sociodemographic variables while weighting and using survey commands to adjust for survey design. The per capita energy intake of less healthy food was higher in high versus medium and low SES (703±8.9 kcal/d; 366±4.3 kcal/d; 144±1.7 kcal/d respectively, p<0.01). These results were consistent with per capita volume purchased of less healthy food (35±0.2 g/d; 25±0.2 g/d; 22±0.2 g/d respectively; p<0.01). Likewise, results were consistent between per capita energy intake and per capita volume purchased of healthy foods when calories from tortillas were not considered (Energy intake: high SES=130±1.2 kcal/d; medium SES=77±0.6 kcal/d; low SES=44±0.3 kcal/d, p<0.01; volume purchased: high SES=25±0.1 g/d; medium SES=16±0.1 g/d; low SES=10±0.2 g/d). The results were opposite when the energy intake from tortillas was included in the healthy food group (high SES=253±3.6 kcal/d; medium SES=416±3.6 kcal/d; low SES=694±5.9 kcal/d, p<0.01). Energy intake from less healthy beverages was higher in high and medium versus low SES (234±3.6 kcal/d; 243±3.5 kcal/d; 104 kcal/d respectively; p<0.01), while the per capita volume purchased of less healthy beverages was lower in high versus medium and low SES (196±0.9 mL/d; 244±1 mL/d; 250±1.8 mL/d respectively; p<0.01). Per capita energy intake and volume purchased of healthy beverages was higher in high versus medium and low SES (Energy intake: high SES=237±1.5 kcal/d; medium SES=167±0.8 kcal/d; low SES=136±0.6 kcal/d, p<0.01; volume purchased: high SES=977±9.3 mL/d; medium SES=866±6.5 mL/d; low SES=654±8.1 mL/d). In conclusion, there is a positive relationship between SES and less healthy food and healthier beverage intake and purchases. In contrast, a negative relationship exists for less healthy beverages.

Support or Funding Information

Funding for this study comes from the Robert Wood Johnson Foundation (Grant 71698) and Bloomberg Philanthropies(grants to University of North Carolina and Mexican National Institute of Public Health)
Differential DNA Methylation between Obese and Normal Weight Women in CD4+ and CD8+ T cells, and CD16+ neutrophils
Authors: Hohos Natalie M , Smith Alicia K , Kilaru Varun , Park Hea Jin , Hausman Dorothy B , Bailey Lynn B , Lewis Richard D , Meagher Richard B
Published: November 2023

Diet, nutrition, and perhaps other lifestyle factors are proposed to alter chromatin structures such as DNA cytosine modification and epigenome‐regulated gene expression. Most dietary and nutritional studies to date analyze DNA cytosine methylation differences in mixed cell populations (i.e. PBMC's or whole blood); however each leukocyte cell type has a distinct DNA cytosine methylation profile. When multiple white cell types are examined together, the methylation data reflect a weight average of all cell types and the biologically meaningful results for each individual cell type are often lost. In order to explore more statistically and biologically significant DNA cytosine methylation data associated with obesity, we examined DNA methylation profiles in three distinct cell types isolated from peripheral blood. CD4+ T cells, CD8+ T cells and CD16+ neutrophils were reiteratively isolated from blood samples in normal weight (BMI 18.5–24.9 kg/m2) and obese (BMI >30 kg/m2 ) women (18–35 y). DNA 5′‐methylcytosine (5mC) levels were measured across > 485,000 CG sites using the HumanMethylation450 BeadChip (Illumina©) for each of the three cell types. After controlling the false discovery rate (q‐value < 0.05), 19 CG sites were differentially methylated between the obese and normal weight women in CD4+ T cells, 16 CG sites in CD8+ T cells and 0 CG sites in CD16+ neutrophils. None of the differentially methylated CG sites overlapped between the CD4+ and CD8+ cells. The amount of visceral adipose tissue (VAT) was found to be associated with the level of methylation in 79 CG sites (q‐value < 0.05) in CD4+ T cells while no differences were found in either of the other cell types. Associations of 5mCs with obesity and VAT ranged from 10−5 < p < 10−9. It appears that the methylome of these three cell types each respond quite differently to obesity and the levels of VAT, illustrating the importance of examining epigenetic marks in single cell types. Among the differentially methylated CGs in CD4+ and CD8+ T cells were sites in genes potentially involved in lipid metabolism (LIAS, ACSM6, AGPAT1, ALDH3B1), metabolic syndrome (SLC2A1/GLUT1, CASZ1, HOXB5, LIAS, LRP1, WNT5B, IGFBP4, RPH3AL, SCARF1), chromatin remodeling (BRD4, SAP30, FANCC, JARID2, PRDM11), Alzheimer's disease (CLSTN1, LRP1), progenitor cell development (FADD, JARID2, LGR5) and the cell cycle (BRD4, MYO10, CDC20B, MAD1L1). In summary, by examining DNA methylation differences in three cell types, we identified highly significant sites that were differentially methylated between the normal and obese weight women with biological relevance to obesity. Future work will continue to characterize response of the DNA methylome to nutrition and lifestyle choices in relation to obesity.
Congenic Mice Confirmed QTL Linked to Obesity and Hyperlipidemia on Chromosome 1 in the TALLYHO Mouse
Authors: Parkman Jacaline K , Mao Xia , Dillon Kristy , Kim Jung Han
Published: November 2023

The TALLYHO (TH) mouse presents a syndrome of obesity, insulin resistance, type 2 diabetes, and hyperlipidemia. In a genome‐wide scan of a [THxC57BL/6 (B6)]F2 population, we previously identified quantitative trait loci (QTL) linked to obesity and hyperlipidemia on mouse chromosome (Chr) 1. To confirm the QTL and develop a strategy for positional cloning of the responsible gene(s), we generated a congenic mouse strain that carries the Chr 1 QTL, 128 Mb in size, derived from TH on a B6 background (B6.TH‐Chr1‐128Mb). Using this congenic strain, we generated a second congenic strain carrying only the proximal segment, 92 Mb in size, of the original congenic interval (B6.TH‐Chr1‐92Mb). The purpose of this study was to characterize these congenic mice on chow and high fat diets (HFD) and evaluate gene expression levels of interferon activated gene 202B (Ifi202b) in these mice as a positional candidate gene. B6.TH‐Chr1‐128Mb congenic, B6.TH‐Chr1‐92Mb congenic and B6 mice were weaned onto chow or HFD and maintained. Body composition and plasma cholesterol and triglyceride levels were determined and indirect calorimetry conducted. The Ifi202b mRNA levels were measured in adipose tissue by qRT‐PCR. On chow, B6.TH‐Chr1‐128Mb congenic mice exhibited significantly larger body fat mass compared with B6.TH‐Chr1‐92Mb congenic and B6 mice. Body fat mass between B6.TH‐Chr1‐92Mb congenic and B6 mice was comparable. Similar trends were exhibited for plasma total cholesterol and true triglyceride levels. These results suggest that the Chr1 QTL candidate region is most likely located within the distal segment of the TH congenic interval where the Ifi202b gene, known to be associated with obesity and extremely down‐regulated in B6 mice due to a microdeletion, maps. All animals gained more body fat when fed HFD than fed chow, but the increase was greater in B6.TH‐Chr1‐128Mb congenic mice than in B6.TH‐Chr1‐92Mb congenic and B6 mice. B6.TH‐Chr1‐128Mb congenic mice showed significantly lower energy expenditure (kcal/kg/hr) than B6.TH‐Chr1‐92Mb congenic and B6 mice on both chow and HFD, without differences in food intake. The Ifi202b mRNA levels were approximately 5‐fold higher in adipose tissue of B6.TH‐Chr1‐128Mb congenic mice than B6 mice on chow, which became even higher on HFD. In summary, TH mice carry QTL conferring obesity and hyperlipidemia on the distal part of Chr 1.

Support or Funding Information

This work was supported in part by NIH/NIDDK Grant R01DK077202, American Heart Association Grant 0855300E, and institutional start‐up funding from Marshall University to JHK.
Exacerbation of NAFLD in both HFD‐fed Mice and MCD‐fed Mice by Adenosine 2A Receptor Deficiency
Authors: Cai Yuli , Zheng Juan , Guo Xin , Li Honggui , Pei Ya , Botchlett Rachel , Woo Shih‐Lung , Liu Mengyang , Chen Guang , Huo Yuqing , Wu Chaodong
Published: November 2023

Non‐alcoholic fatty liver disease (NAFLD) is an essential component of metabolic syndrome. Much evidence has demonstrated that the incidence of NAFLD is markedly increased in obese populations. In addition, adiposity and inflammation are two factors that critically contribute to the development and progression of hepatic steatosis and inflammatory damage in obesity‐associated NAFLD. While mediating the anti‐inflammatory activity of adenosine, the 2A receptor of adenosine (A2AR) also has a protective role in NAFLD. However, it remains largely unknown about the extent to which A2AR acts through altering adiposity vs. inflammation to protect against NAFLD. In the present study, the effects of A2AR deficiency on aspects of NAFLD were investigated in both obese mice and lean mice upon feeding wild‐type (WT) C57BL/6J mice and A2AR‐deficent mice a high‐fat diet (HFD) and/or a methionine‐ and choline‐deficient diet (MCD). Compared with low‐fat diet‐fed mice, HFD‐fed WT mice displayed overt hepatic steatosis and inflammation as indicated by increased proinflammatory signaling and cytokine expression. Furthermore, the severity of HFD‐induced hepatic steatosis and inflammation in A2AR‐deficient mice was much greater than that in WT mice, which was accompanied with increased body weight, adiposity, and adipose tissue infiltration of proinflammatory macrophages in HFD‐fed A2AR‐deficient mice. Unlike HFD‐fed mice, all MCD‐fed mice displayed lean phenotype due to a significant decrease in food intake. In the absence of adiposity, A2AR‐deficient mice still displayed a greater increase in the severity of hepatic steatosis and inflammation compared with WT mice. In an in vitro system, A2AR‐deficient macrophages showed an increase in proinflammatory responses compared with control cells. In addition, co‐culture of WT primary mouse hepatocytes with A2AR‐deficient macrophages caused significant increases in hepatocyte fat deposition and in hepatocyte proinflammatory responses compared with WT hepatocyte‐macrophage co‐cultures. Taken together, these results suggest that A2AR‐defiency‐associated inflammation is sufficient enough to bring about NAFLD aspects although A2AR deficiency can act through increasing both adiposity and inflammation to exacerbate NAFLD. Therefore, A2AR appears to protect against NAFLD mainly through its anti‐inflammatory activity.

Support or Funding Information

This study was support in part by NIH grants.
Protein and micronutrient intakes are associated with child growth and morbidity from infancy to adulthood in the Philippines
Authors: Bhargava Alok
Published: November 2023

Background

Interactions between nutrition and infections in developing countries are complex and analyses of the inter‐relationships requires data from longitudinal studies spanning several years and a comprehensive framework facilitating the formulation of food and health policies.

Objective

The effects of dietary intakes in the Philippines for birth outcomes, heights, weights and morbidity during 2–24 mo, heights and weights during 8–19 y, and completed adult heights were analyzed.

Methods

Data on over 3000 children from Cebu Longitudinal Health and Nutrition Survey were modeled in four sets of analyses. Cross‐sectional and multilevel models were estimated for length and weight at birth. Dynamic random effects models were estimated for children's heights, weight, and morbidity levels during 2–24 mo. Children's heights and weights during 8–19 y were modeled using random effects models. Children's heights at 22 y were modeled for investigating the effects of nutritional intakes in early years and in adolescence.

Results

Maternal anthropometric indicators and energy intakes and sociodemographic variables were significantly associated with children's length and weight at birth. Dynamic models for children's heights and weights during 2–24 mo showed significant effects of calcium and protein intakes; child morbidity levels were significantly associated with heights and weights. Higher β– carotene intakes were significantly associated with lower morbidity levels. Analyses of data on children during 8–19 y showed significant effects of protein and calcium intakes and of morbidity levels on heights and weights. Models for children's heights at 22 y indicated significant effects of protein and calcium intakes during early years and in adolescence.

Conclusions

The results underscored the need for formulating long‐term food and health policies for the Philippines that enhance children's physical development and ultimately their adult stature that is important for physical work capacity and labor productivity.
Camp NERF: Efficacy of a Theory‐Based Nutrition Education Recreation and Fitness Program Aimed at Preventing Unhealthy Weight Gain in Disadvantaged Children during Summer Months
Authors: Hopkins Laura Christine , Gunther Carolyn
Published: November 2023

Background

Data indicate that school‐age children, particularly disadvantaged, experience unhealthy gains in BMI at a rate two to three times as fast during the summer versus academic months. Few efforts have been directed at implementing evidence‐based programming to prevent this negative trend.

Study Design and Methods

Pilot tested in 2015, Camp NERF 2016 was a citywide scale up of an 8‐week, multi‐component (nutrition, physical activity (PA), and mental health), theory‐based program for disadvantaged school‐age children in grades K‐5coupled with the USDA Summer Food Service Program. Ten eligible elementary school sites were randomized to 1 of 3 programming groups: 1) Active Control (non‐nutrition, PA, or mental health); 2) Standard Care (nutrition and PA); or 3) Enhanced Care (nutrition, PA, and mental health) programming. Program efficacy was determined by assessing mean group change in weight status (zBMI) using hierarchical linear model analyses.

Results

Eighty‐seven child‐caregiver dyads consented to the study and 81 completed post‐intervention assessments, resulting in a 93% retention rate. Among child participants, approximately 56.2% (n=49) were female and 89% (n=77) were Black. Mean age and zBMI of participants at baseline were 7.5 years and 0.64, respectively. The overall mean change in zBMI from baseline to post‐intervention was −0.07; however, change in zBMI did not differ statistically between groups.

Conclusions

Results from this study indicate that engagement of disadvantaged school‐age children in structured programming over the summer months that offers access to healthy foods and safe play, as well as a child‐appropriate curriculum – of any type (nutrition, PA, mental health, other) – prevents unhealthy weight gain during non‐academic months. To confirm findings from this study, further research which includes a true negative control (i.e., observation of child counterparts who do not participate in summer programming) must be conducted. Results from this research have direct implications for policy reform related to child foods and nutrition.

Support or Funding Information

The Camp NERF research team would like to thank the Aetna Foundation and The Ohio State University Office of Outreach and Engagement for funding this pilot study.
Upregulation of the Multidrug Resistance P‐glycoprotein ABCB1 by Transcription Factor Pituitary Homeobox 2 (Pitx2) in Human Colon and Kidney Cancers
Authors: Lee Wing‐Kee , Thévenod Frank
Published: November 2023

Background

Pituitary homeobox 2 (Pitx2) is a master regulator of organ asymmetry during development but is reactivated in neoplastic cells, contributing to cell proliferation, tumor cell invasion and cancer progression. Upregulation of the multidrug resistance P‐glycoprotein ABCB1 confers chemotherapeutic drug resistance to tumor cells, hampering effective treatment. We have previously shown that Pitx2 is upregulated in a multidrug resistant (MDR) kidney cancer cell line and serves as a positive transcriptional regulator of ABCB1 thereby increasing resistance to the anthracycline chemotherapeutic drug, doxorubicin (DOX) (Lee, W.‐K. et al. Int J Cancer 113, 556–67, 2013). The objective of this study was to determine if ABCB1 regulation by Pitx2 is also in engaged by other cancer types that exhibit intrinsic MDR.

Methods

Expression of Pitx2 and ABCB1 was determined by immunofluorescence microscopy, immunoblotting and immunohistochemistry. Cell viability was assessed by MTT and clonogenic survival assays. Pitx2 transcriptional activity was measured by luciferase reporter gene assay. Isolation of nuclei was performed by Tenbroeck homogenization in hypoosmotic buffer and a discontinuous sucrose gradient.

Results

In human colorectal adenocarcinoma Colo320DM cells, which exhibit MDR and harbor augmented ABCB1 expression, nuclear Pitx2 expression and Pitx2 reporter gene activity were significantly increased compared to less drug resistant Colo205 cells. The ABCB1 inhibitor PSC833 (0.1 μM) reversed drug resistance to 1 μM DOX after 24 h in Colo320DM cells. Further, knockdown of Pitx2 by RNAi in Colo320DM cells resulted in decreased ABCB1 protein by almost 3‐fold and diminished resistance to DOX resulting in attenuated cell survival. Moreover, the Pitx2 isoforms that are involved in regulation of ABCB1 in colon and kidney cancer cells were investigated. Both Pitx2A and Pitx2B were found to be present in the nuclear fraction of Colo320DM and MDR A498 kidney carcinoma cells. Analysis of human kidney and colon cancer tissue arrays by co‐immunostaining suggests a causal relationship between nuclear Pitx2 and ABCB1 expression.

Conclusion

Pitx2 is a transcriptional regulator of ABCB1 in cancers of the colon and kidney suggesting a contributory role to the MDR phenotype.

Support or Funding Information

Funded by an Internal Research Grant (UW/H) and ZBAF
The Role of Twist1 Phosphorylation in Tumor Angiogenesis in Lung Cancer
Authors: Mammoto Tadanori , Jiang Amanda , Jiang Elisabeth , Mammoto Akiko
Published: November 2023

Lung cancer is the leading cause of cancer death in the US and the survival rate for advanced lung cancer patients is very low. Deregulated angiogenesis ‐the formation of new blood capillaries from existing blood vessels‐ contributes to lung cancer; however, current anti‐angiogenic therapy has potential problems such as rebound tumor growth and resistance to therapy. Here we implant fibrin gel containing either lung tumor‐derived factors or a small pellet of lung cancer cells on the mouse lung and show that a transcription factor, Twist1, mediates tumor angiogenesis through the VEGF‐VEGFR2 pathway. Conditioned media from lung cancer cells upregulate Twist1 Ser42 phosphorylation in endothelial cells (ECs), and Twist1 knockdown or inhibition of Twist1 Ser42 phosphorylation using a mutant construct (Twist1S42A) decreases VEGFR2 expression and EC sprouting induced by conditioned media in vitro. Tumor angiogenesis is also inhibited in fibrin gel implanted on Tie2‐specific Twist1 conditional knockout mouse lungs or Twist1S42A‐treated mouse lungs in vivo. These results suggest that Twist1 Ser42 phosphorylation plays a key role in tumor angiogenesis associated with lung cancer, and modulation of Twist1 Ser42 phosphorylation could be a potential therapeutic strategy for lung cancer.

Support or Funding Information

Boston Children's Hospital Career Development Award
A Novel Signaling Pathway that Governs Tumor Metastasis: Ceramide Regulates Direct Crosstalk Between TGF‐ß and Sonic Hedgehog Signaling
Authors: Gencer Salih , Ogretmen Besim
Published: November 2023

In the past twenty years, specific sphingolipids have become recognized for their participation in membrane functions and signaling events that control a wide array of cellular processes. Ceramide is considered as a main molecule of bioactive sphingolipid metabolites, are involved in signaling pathways that regulate cell proliferation, apoptosis, motility, differentiation, and angiogenesis. More recent studies have introduced bioactive sphingolipids and their metabolic enzymes take a role as regulated component in migration and cell mobility processes. However, the molecular mechanism of ceramide involved is unknown. Here, we investigated the effect of ceramide synthases (CerS) and ceramide on migration and its related signal pathways in situ and in vivo model. Interestingly, our data show that among CerS only CerS4/ceramide is involved to cell migration and tumor metastasis. Here, we also have generated CerS4−/− mice for in vivo studies. Excitingly, we observed that genetically loss of CerS4 resulted in severe irreversible alopecia, which was associated with hyper‐proliferation and migration of keratinocytes. Mechanistically, we show here that genetic loss or shRNA‐mediated knockdown of CerS4 enhances cell migration by which ligand‐independent signaling of TGF‐beta receptors I and II (TßRI/II) in various cell types, including keratinocytes, mouse embryonic fibroblasts and cancer cells. Mechanisms that regulate membrane localization of TßRI/II for the regulation of cell migration and metastasis are largely unknown. We identified that alterations in ceramide metabolism by molecular knockdown and/or genetic deletion of CerS4, reducing bioactive C18‐C20‐ceramides, results in enhanced TßRI‐II signaling at the plasma membrane by inhibiting Smad7 recruitment to the receptor, leading to increased cell migration/invasion via activation of the sonic hedgehog (Shh) pathway. Mechanistically, inhibition of Smad7‐TßRI/II interaction in response to CerS4 knockdown led to the activation of the Shh signaling via enhanced association/cross‐talk between TßRI‐II and smoothened (Smo), a signaling Shh receptor, at the plasma membrane. In reciprocal studies, reconstitution of CerS4/ceramide inhibited TGF‐ß‐Shh crosstalk, reducing cancer cell migration and inhibition of the cancer cell colonization/lung metastasis in SCID mice. Moreover, knockdown of CerS4 in cancer cells, but not systemic deletion of CerS4 in mice, increased metastasis of breast cancer cells from mammary pads to the liver, which was inhibited by Smad7 expression or Smo knockdown. Thus, these data reveal that CerS4/ceramide is a novel factor that regulates the recruitment of Smad7 to the TßRI, controlling the stability/surface expression of the receptor, which modulates TßRI/II‐Smo crosstalk, controlling cell migration and cancer metastasis.

Support or Funding Information

1R01 DE016572
Epigenetic regulation of epithelial cellular fate by CTBP
Authors: Byun Jung S , Gardner Kevin
Published: November 2023

Epithelial phenotype is a default state of epithelial cells. The shift between epithelial and mesenchymal phenotypes is one of the hallmarks of cancer. Epithelial cells retain incredible plasticity. They can differentiate and self‐renew during embryonic and post‐natal organ development. An essential developmental process is the ability to weaken their typical epithelial features and change to a mesenchymal state by activating epithelial to mesenchymal transition (EMT), a program that is abnormally activated during tumor progression and metastasis, yet is required for effective tissue repair. This plasticity has central implication for the dysregulation of epithelial and mesenchymal states that leads to cancer initiation and progression.

C‐terminal binding protein (CTBP) is an epigenetic regulatory protein that controls gene expression in response to metabolic imbalance. It is activated in the presence of NADH to recruit and target a variety of histone modifying complexes and transcriptional regulators to chromatin, thus providing a defined network of interactions that modulate cellular programming. Recently, we have found that CTBP controls major cancer hallmark pathways including genome instability, EMT, and tumor initiating cells and stemness. In order to define the mechanisms through which CTBP controls cellular plasticity, we compared non‐tumorigenic human breast epithelial MCF10A cells with CTBP‐depleted MCF10A. Using this system, we characterized several molecular biological and biochemical properties driven by CTBP in correlation with genome‐wide profiling by ChIP‐Seq and RNA‐Seq.

In this study we illustrate that CTBP depletion enhances epithelial differentiation and upregulates epithelial gene expression and CTBP overexpression shifts differentiation from epithelial to mesenchymal in mammary epithelial cells. Furthermore, we find that CTBP plays an important role in influencing epithelial plasticity mediated by DNA methylation inhibition, thus providing a conceivable opportunity for enhanced therapeutic intervention.
AA Amyloidosis In Island Foxes (Urocyon Littoralis): Pathology, Risk Factors, And The Genetic Basis For Disease
Authors: Gaffney Patricia , Witte Carmel , Clifford Deanna , Ghassemian Majid , Gaasterland Terry , Sigurdson Christina
Published: November 2023

The island fox (Urocyon littoralis) is an endangered species that lives exclusively on the California Channel islands. Island foxes inhabit six of the eight Channel islands and have evolved into six genetically distinct, island‐specific subspecies. Systemic amyloidosis is highly prevalent in island foxes and is a threat to species recovery. I have identified the type of amyloid, described the lesions of amyloidosis in foxes, and investigated the risk and underlying molecular mechanisms of disease. Based on immunoreactivity to anti‐canine AA antibody and protein sequencing by mass spectrometry, amyloid in foxes has been identified as amyloid A (AA). AA amyloidosis occurs following prolonged elevation of the acute phase protein serum amyloid A (SAA), secondary to chronic infectious or inflammatory disease. Amyloid aggregates in tissue were most common in kidney, spleen and the oral cavity, and amyloid in foxes had a propensity for deposition along basement membranes. Sequencing of the SAA protein identified it as a 111 amino acid long protein with multiple isoforms and an amyloid‐prone, N‐terminal segment. Risk factors for disease were identified by multivariable logistic regression as older age, the San Clemente island subspecies, captivity and nephritis. Increased risk for disease in one subspecies, in addition to the lack of reports of AA amyloidosis in gray fox, the closest genetic relative to island fox, suggest a possible genetic association with disease. Examination of gene transcript levels in the SAA transcription pathway revealed SAA, IL6, IL1α, IL1β, and C/EBP‐δ transcripts were significantly elevated in island foxes with AA amyloidosis, and higher SAA transcripts correlated with more severe disease. Serum SAA protein concentrations were similar in foxes that died with and without amyloidosis, suggesting serum protein levels are not an accurate indicator of disease status. Lastly, based on sequence variation in the region of the SAA gene family in island and gray foxes, 14 SNPs unique to all island fox subspecies have been identified. Understanding the influence of genetic as well as exogenous factors on AA amyloidosis in island foxes informs not only on the disease mechanism in this endangered species, but contributes to the overall understanding of the pathogenesis of AA amyloidosis.

Support or Funding Information

This work was supported by an Academic Senate Grant from the University of California, San Diego, the Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, and the ARCS Foundation of Northern California. P.M.G was funded by The Linda Munson Fellowship for Wildlife Pathology Research administered by the ACVP/STP Coalition for Veterinary Pathology Fellows and the Peter Kennedy Fellowship in Anatomic Pathology, School of Veterinary Medicine, University of California, Davis.
Regulation of gene expression by complex RNA molecules
Authors: Pyle Anna M.
Published: November 2023

While we typically think of proteins as highly structured molecules, we often don't think about RNAs in the same way. Recent advances in studies of ribozymes, riboswitches, and large RNA‐protein complexes such as the ribosome have changed this view and made it clear that RNA molecules can adopt elaborate structures that form enzyme active‐sites, architectural scaffolds, and ligand‐gated machines. Even messenger RNAs (mRNAs) can be highly folded, suggesting a “code within the genetic code” that contributes to regulated gene expression. Much of our knowledge about RNA structure comes from chemical probing experiments and crystallographic studies on large ribozymes, such as self‐splicing group II introns. These studies have revealed a set of building blocks from which RNA molecules can assemble into compact, well‐folded structures. RNA structural motifs can control transcription, translation and even splicing of a gene. Recently, understanding of RNA functional diversity was further expanded by the discovery that our genomes are almost completely transcribed, and that we express numerous long noncoding RNA transcripts (lncRNAs). While the function of these giants is being actively investigated, it is clear that many of them facilitate epigenetic control of gene expression. Given the significance of lncRNAs, and of other large RNAs such as viral RNA genomes, the architectural complexity of these behemoths has become an important question. Secondary and tertiary structures within large RNAs may reveal new pathways for regulating gene expression and provide new targets for the design of small molecule modulators.

Support or Funding Information

HHMI and the NIH