bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxylipids derived from arachidonic and dihomo‐gamma‐linolenic acids are associated with colon polyps in adult males
Authors: Yin Zhe , Pickens C. Austin , Sordillo Lorraine M , Fenton Jenifer I.
Published: November 2023

Oxylipids are potent lipid mediators associated with inflammation‐induced colon carcinomas and colon tumor survival. Therefore, oxylipid profiles may be useful as biomarkers of colon polyp presence. The aim of the study was to investigate the relationship between plasma non‐esterified oxylipids and the presence of colon polyps. A total of 123 men aging from 48 to 65 were categorized into 3 groups: those with no polyps, those with 1 or more hyperplastic polyps, and those with 1 or more adenomas. Plasma non‐esterified oxylipids were analyzed using solid phase extraction and quantified using a targeted HPLC tandem mass spectrometric analysis. Statistical analyses included Kruskal‐Wallis one‐way ANOVA with Dunn's test for multiple comparison and generalized linear models. In general, monohydroxy oxylipids derived from the omega‐6 family were significantly increased in those with polyps. Concentrations of 5‐hydroxyicosatetraenoic acid (HETE), 11‐HETE, 12‐HETE, 15‐HETE and 15‐hydroxyeicosatrienoic acid (HETrE) were significantly higher in those with hyperplastic polyps (4.86 nmol, 0.93 nmol, 12.11 nmol, 1.02 nmol, and 0.33 nmol respectively) and adenomas (4.61 nmol, 0.81 nmol, 10.05 nmol, 0.93 nmol, and 0.44 nmol respectively) compared to those with no polyps (1.86 nmol, 0.39 nmol, 7.83 nmol, 0.63 nmol, and 0.24 nmol respectively). On the other hand, the concentration of endocannabinoid arachidonyl ethanolamide (AEA), derived from the non‐oxidative metabolism of arachidonic acid, decreased significantly in those with adenomas (0.18 nmol) compared to those with hyperplastic polyps (0.25 nmol). Even after adjusting for age and smoking in regression models, these oxylipids remained significantly associated with polyps. Since many of these oxylipids are formed through oxygenation by lipoxygenases (i.e., 5‐, 12‐, and 15‐HETE, and 15‐HETrE) or auto‐oxidative reactions (i.e., 11‐HETE), this may indicate that lipoxygenase activity and lipid peroxidation are increased in those with colon polyps. In addition, since oxylipids such as 5‐, 12‐, and 15‐HETE and AEA are signaling molecules involved in inflammation regulation, these oxylipids may have important functions inflammation‐associated polyp formation. Future studies should investigate if these oxylipids may be useful as potential biomarkers of colon polyps, and verify our findings in larger and more diverse populations.

Support or Funding Information

Funding sources NIH R03CA142000
The proliferation and invasion of low passage number human colon cancer cell lines is inhibited by retinoids
Authors: Martinez Marissa M. , Hurst Alexandra , Reynolds C. Patrick , Lane Michelle A.
Published: November 2023

Previously we examined how vitamin A and its metabolite, all‐trans‐retinoid acid (ATRA), inhibit the proliferation and invasion of commercially available human colon cancer cell lines. Commercial cell lines may be suboptimal models, because they have been in culture for many passages. Our goal was to determine if low‐passage patient‐derived colorectal cancer cell lines (TX‐CC‐208 and TX‐CC‐286) also responded to retinoids. To determine if retinol and ATRA inhibited proliferation, 24 hours after seeding, cells were treated with 0 (vehicle control), 1, or 10 μM retinol or ATRA for 72 hours. TX‐CC‐208 cell number was decreased to 62.1 ± 3.1% of control regardless of retinoid type or concentration. Similarly, the number of TX‐CC‐286 cells was decreased to 51.8 ± 3.9 percent of control. TX‐CC‐208 cells were not invasive. The invasion of TX‐CC‐286 cells through Matrigel‐coated Boyden chambers was decreased to 40 ± 1.2% of control following 72 h of treatment with retinoids regardless of type or concentration. In conclusion, low‐passage (pass 7–17) patient‐derived colorectal cancer cell lines exhibited decreased proliferation and, in one cell line, invasion, in response to retinoid treatment. Both cells lines were sensitive to ATRA, suggesting they express retinoic acid receptors. These receptors are often not found in commercially available colon cancer cell lines, particularly invasive cell lines. These data suggest that retinol and ATRA may decrease the growth and metastasis of colon cancer in vivo. We are currently working to determine if ATRA mediates the ability of retinol to inhibit cell proliferation and invasion.

Support or Funding Information

This research was supported by donations from the Heather Custer Memorial Fund and Kiel Colon Cancer.
Greater Perseverance and Determination Predicts Lower Odds of Food Insecurity in Households with Children
Authors: Nikolaus Cassandra Jean , Schierer Megan Jean , Nickols‐Richardson Sharon M
Published: November 2023

Food insecurity (FI), defined as the lack of access to culturally appropriate and adequate food to meet an individual's (or family's) needs, is often considered an international concern, but it continues to persist in developed countries. Diet quality and subsequent health of millions of American adults and children are threatened by household FI. Previous work has consistently established a negative relationship between household income and risk of FI. However, a small portion of households below the poverty line are able to maintain food security despite limited incomes. This has inspired researchers to investigate determinants, beyond income, that predict lower odds of household FI. The aim of this study was to investigate grit (a measure of two non‐cognitive traits: perseverance and determination) as a predictor of FI risk among a cross‐sectional sample of parents. An online questionnaire was designed to assess: 1) household FI using the 18‐item Household Food Security Survey Module; 2) perseverance and determination using the validated 8‐item Grit‐S questionnaire; and 3) several previously established predictors of FI (race, ethnicity, household size, education, marital status, health insurance, and income). This questionnaire was distributed to an online panel of U.S. consumers (Qualtrics LLC.). To be eligible, parents needed to have at least one child under the age of 18 years in the household and an overall household income below the 2015 median household income ($52,250 U.S. dollars per year). All statistical analyses were conducted using STATA/MP 14.1 (StataCorp LP); significance was set to α=0.05. Within the sample of n=252 parents, 61.1% reported household FI. Mean (±SD) Grit‐S was 3.35 (±0.62), on a scale of 1 (low grit) to 5 (high grit). Logistic regression was used to predict household FI from parent's Grit‐S score and established covariates. Overall, the model had a R2=0.08, and parent's Grit‐S score significantly decreased the odds of household FI (β= −1.12; 95% CI= −2.02, −0.23; P= 0.01); no other variables were significantly associated with FI. These results suggest that parent's perseverance and determination (as measured by Grit‐S) may be a valuable determinant of household FI. Future research should investigate whether these results are consistent when repeated in a larger and more diverse sample.

Support or Funding Information

N/A
Consumption of whole aronia berry powder inhibits adoptive transfer‐induced colitis in mice
Authors: Pei Ruisong , Martin Derek , Bolling Bradley
Published: November 2023

Background

Aronia berries are rich in polyphenols which may inhibit inflammation by modulating gut immunocyte function. However, the mechanisms responsible for this effect is unclear.

Objective

To identify the effects of aronia consumption on intestinal inflammation and T cell populations in the mouse adoptive transfer model of colitis.

Design

Recombinase activating gene (RAG)−/− mice were obtained at 4 wk age and were acclimatized for 2 weeks prior to experiments. Live CD4+CD45RBhigh cells were obtained by magnetic activated cell sorting (MACS) from gender and age‐matched syngeneic C57BL6 mice and transferred to RAG1−/− mice by intraperitoneal (IP) injection. Injected RAG1−/− mice were randomly assigned to receive a control or 4.5% w/w lyophilized ‘Viking’ aronia berry supplemented diet (n = 21/group). A negative control group of RAG−/− mice were injected with sterile phosphate‐buffered saline (PBS) as the sham group (n = 21). Body weight (BW) and food intake were recorded twice a week. Groups of mice were sacrificed at 7–8 wk post injection. Colons were collected for weight and length measurement. Lamina propria lymphocytes (LPL) and mesenteric lymph nodes (MLN) were isolated from colon and analyzed by flow cytometry to determine Th17 and Treg populations.

Results

BW declined at 4 weeks after CD4+CD45RBhigh transfer, and was accompanied by reduced food intakes. The aronia diet prevented colitic weight loss. Control BW decreased to 82.5% at wk 7, whereas the aronia‐fed mice decreased to 93.2% BW at wk 7. Intestinal inflammation was evident by noticeable increases in colon weight/length ratios compared to sham. Aronia consumption inhibited increases in colon weight/length ratios relative to the control (0.042 ± 0.008 vs. 0.058 ± 0.006 g/cm). MLN and LPL Treg populations in both groups of colitic mice did not differ from that in the sham. The total Th17 in LPL but not MLN was higher in aronia group than the control (P = 0.0216, n = 5–7/group).

Conclusion

Whole aronia berry consumption reduced wasting in T‐cell transfer‐induced colitis, and increased Th17 but not Treg populations in LPL.

Support or Funding Information USDA NIFA AFRI WIS01909
Elevated Muscle Inflammatory Response After Protein‐Dense Food Ingestion in Obese Adults
Authors: Skinner Sarah K , Beals Joseph , Van Vliet Stephan , Niemiro Grace M , Dilger Anna C , De Lisio Michael , Paluska Scott , Burd Nicholas A
Published: November 2023

Skeletal muscle inflammation related to alterations in the toll‐like receptor 4 (TLR4) signaling may lead to insulin resistance and poor muscle remodeling. However, the effect of food ingestion on modulating TLR4/ myeloid differentiation factor 88 (MyD88) signaling with or without excess fat mass has not been examined. Therefore, we examined skeletal muscle TLR4 and MyD88 protein content before and after protein‐dense food ingestion across a range of body mass indexes (BMIs) in healthy, sedentary adults. Eight healthy‐weight (HW: age; 25±1 y, BMI: 23.0±0.4 kg/m2, HOMA‐IR: 1.3±0.2), 8 overweight (OW: age; 25±2 y, BMI: 27.3±0.4 kg/m2, HOMA‐IR: 1.3±0.1), and 8 obese (OB: age; 29±3 y, BMI; 36.0±1.4 kg/ m2, HOMA‐IR: 6.1±0.8) men and women ingested 170 g of lean pork (36 g protein, 3 g fat). Repeated blood samples and muscle biopsies were collected from the vastus lateralis in the basal‐state and over a 5 h postprandial period. Plasma non‐esterified fatty acid (NEFA) concentrations declined during the postprandial period and these values did not differ between groups (P=0.61). Skeletal muscle TLR4 and MyD88 protein content were not different between groups at baseline (P>0.05). However, pork ingestion increased muscle TLR4 (1.9‐fold from baseline) and MyD88 protein content (1.6‐fold from baseline) (both P<0.05) in the OB group at 5 h of the postprandial period when compared to the OW and HW groups. These data show that food ingestion modulates the muscle inflammatory effect related to TLR signaling in obese adults, but not overweight and healthy weight adults, and appears to be independent of circulating plasma NEFA concentrations. The elevated muscle inflammatory response to food ingestion may, at least partly, contribute to the impaired postprandial glucose and protein handling commonly observed in obese adults.

Support or Funding Information

The National Pork Board
High‐Fat Diets Enriched with Varying Fatty Acid Compositions Have Differential Effects on Skeletal Muscle Troponin T pre‐mRNA Alternative Splicing
Authors: Black Adam , Schilder Ruud , Kimball Scot
Published: November 2023

Alternative splicing (AS) of pre‐mRNA allows for a significant expansion of the proteome from a limited number of protein coding genes. Skeletal muscle Troponin T (Tnnt3) is known to be highly alternative spliced and expression of Tnnt3α splice forms in muscle has been shown to engender increased sensitivity to calcium‐induced muscle contraction and force production compared to Tnnt3β splice forms. We have previously shown that in the rat gastrocnemius, Tnnt3 AS is adjusted in a quantitative fashion in response to natural and experimental increases in body mass and these responses are impaired in obese rats. Therefore, the goal of the current study was to assess whether or not fatty acids or their downstream metabolites alter the pattern of Tnnt3 AS. In these studies, rats were fed either a 10% or 45% fat diet enriched with various types of fat (i.e. lard, saturated, mono‐, or poly‐unsaturated fats) for two‐weeks and the pattern of Tnnt3 AS in the gastrocnemius/plantaris complex was assessed. Rats fed high fat diets enriched with lard expressed significantly less Tnnt3α isoforms and more Tnnt3β isoforms compared to rats fed control lard diets. Rats fed high fat diets enriched with saturated fats had a similar trend in Tnnt3 AS. Interestingly, the high fat diet‐induced effects on Tnnt3 AS were not observed in rats fed diets enriched in mono‐or poly‐unsaturated fatty acids, suggesting that diets with varying fatty acid compositions have differential effects on Tnnt3 AS and that dietary saturated fatty acids may be driving this effect. To assess the possibility that saturated fat was acting directly on muscle to promote changes in AS, L6 myotubes were treated with either a saturated fat (palmitate), a monounsaturated fat (oleate), or a polyunsaturated fat (linoleate) for 24 h. Palmitate treatment caused a significant change in Tnnt3 AS as well as a 50% reduction in phosphorylation of Akt S473. In contrast, treatment with either oleate or linoleate had differential effects on Tnnt3 AS compared to palmitate treated myotubes and had no effect on Akt phosphorylation. Treatment with a downstream metabolite of palmitate, ceramide, had effects similar to palmitate on Tnnt3 AS and Akt phosphorylation. Moreover, co‐treatment with an inhibitor of ceramide biosynthesis attenuated the palmitate‐induced changes in AS. Overall, we show that varying the fatty acid composition of the diet can alter Tnnt3 AS and that in vitro fatty acids can directly and differentially alter Tnnt3 AS and signaling pathways important in skeletal muscle. Further elucidation of the environmental and intra‐ and extracellular signals regulating Tnnt3 AS will help us better understand the development of obesity induced muscle pathologies.

Support or Funding Information

NIH (DK‐094141)
Athletes' Attitude on Foods as Snacks
Authors: Okumura Yuka , Okamura Koji , Miyazaki Shiho , Ishihara Kengo , Yokota Yukari , Matsumoto Megumi
Published: November 2023

Food guidelines, such as the food pyramid, show that sweets, salty snacks and sweetened drinks can be consumed sparingly or moderately. However, some studies report that athletes restrict these foods. The purpose of this study was to investigate what kind of foods were considered to be favorable or unfavorable as a snack for athletes. A questionnaire listing 35 foods (classified into 6 groups: [1] rice and noodles, [2] breads, [3] processed foods, [4] dairy products, [5] sweets and salty snacks and [6] fruits and drinks) was completed by 469 university athletes (345 males and 124 females) aged 19.2±1.22 years. Comparisons were made between sexes, the requirement for weight management in their sport (weight), the receipt of nutrition advice (advice), and the level of self‐evaluated nutrition knowledge (knowledge). More than half of the subjects answered ‘unfavorable’ for 11 foods: instant noodles, hamburger, carbohydrate‐rich pastries, fatty pastries, fried foods, confectionery, cookies, ice cream, candy and gum, salty snacks, and sweetened drinks, with no significant differences in responses based on sex, weight, advice, or knowledge. However, females regarded udon/soba/soumen (Japanese noodles), donburi (a rice bowl with meat, fish, or vegetables), pasta, sandwiches, steamed meat buns, processed meats, and canned/dry fruits as unfavorable more often than males (p < 0.05). Furthermore, less than 50% of females thought that pasta was favorable. Energy drinks were considered unfavorable by subjects who had received nutrition advice (p < 0.05). The subjects evaluated foods rich in sugar and fat, such as salty snacks, sweets, fried foods, and sweetened drinks, which they had been instructed to consume sparingly or moderately, as less favorable, and these foods were not generally consumed as daily meals. Females tended to regard foods rich in carbohydrates and protein that were recommended by dietitians as less favorable than males.
Energy intake during the Last Supper: Insights from Mathematical Models
Authors: Aselton Chris , Thomas Diana , Salinas Antonio
Published: November 2023

Background

Historical research and reliance on descriptions in the Bible provide insight into the kinds of foods that may have been consumed during the Last Supper. However, little is known regarding energy intake during this era.

Methods

We first applied historical food records to estimate the habitual energy intake. Using ancient Roman estimates of height from military recruitment records and life expectancy, we employed Waaler surfaces to algebraically back calculate body weight. A range of plausible PAL for males was derived from direct measurements in modern day agrarian cultures. Using the range of plausible physical activity levels (PAL) and estimated resting metabolic rate (RMR) from the Mifflin St. Jeor, Harris Benedict, and Livingston Kohlstadt models we derived lower and upper bounds for estimated habitual energy intake during the period of the Last Supper.

Results

Food records in the Mishnah tractate Ketubboth describes a minimum weekly diet for a woman when her husband was absent: two cobs of wheat (2.2 liters), half a cob of pulse (1.1 liters), half a log of oil (.5 liters), and one cob (1.1 liters) of dried figs or other fruit. A rough translation of these amounts into habitual daily intake averages to 1176 kcal/d. This estimate is below the cost to sustain life and implausible. Minimum height for Roman military recruits was approximately 163 cm and a rough estimate of height within the Roman army was 170 cm. Life expectancy was approximately 35 –45 years. Back calculation of the life expectancy from Waaler surfaces yielded a range of body mass index from 19–21 kg/m2. Range of weight was then computed to be 50.5 to 60.7 kg. The range of PAL obtained from Bolivian farmers was estimated between 1.65–2.51. The range of energy intake derived from the three different RMR models and ranges of PAL yielded daily intake as 2319 – 3973 kcal/d.

Conclusions

Historical records can provide information on what types of foods may have been consumed; however, the information is sparse and yields physiologically implausible values for habitual intake. The mathematical approach here can inform historical research by filling this gap.
Self‐reported Stress is Not Associated with Functional Magnetic Resonance Imaging Food‐cue Reactivity in Adults with Obesity
Authors: Quarles William R , Kahathuduwa Chanaka Nadeeshan , Davis Tyler , O'Boyle Michael , Binks Martin
Published: November 2023

Background

Previous studies have suggested that stress influences ingestive behavior in people with obesity. We hypothesized this may in part be influenced by heightened reactivity to food cues.

Objective

To examine the association between self‐reported levels of stress and brain functional magnetic resonance imaging (fMRI) food‐cue reactivity (FCR).

Methods

Baseline data of 32 adults with obesity (age 19–65 yrs.; BMI 30–39.9kg/m2) was used from a larger study. Subjects rated their self‐reported perceived stress level in relation to household and work environments using 1–5 Likert‐scales (part of a larger demographic, health & weight history form). The subjects underwent an fMRI scanning session while rating 240 images (120 food and 120 objects) presented in an event‐related paradigm. Household and work environment stress scores were combined, and the mean of those scores was used to create a composite stress score. Subjects were then divided into two groups based on their composite stress score, using the median as the cutoff. FMRI analyses were conducted using FSL, in a three‐level model, to compare food‐cue reactivity of high vs. low stress groups. In separate analyses we compared high stress and low stress group associations with the following pre‐hypothesized regions of interest: amygdala, hippocampus, anterior cingulate cortex, orbitofrontal cortex, insula.

Results

FMRI analysis did not reveal any significant differences in FCR at the whole brain level or in pre‐hypothesize regions of interest.

Conclusion

While previous behavioral studies have suggested that stress influences ingestive behavior, we found no significant association of self‐reported stress with food‐cue reactivity in our sample of individuals with obesity. Therefore, our findings suggest that heightened food‐cue reactivity may not be a salient contributor to the previously noted relationship of stress to ingestion. However, further research is needed to more fully investigate the likely multidimensional contributors to this phenomenon.

Support or Funding Information

Funding: Nestle Health Science.
Safety and Efficacy of a Novel Green Coffee Bean Extract (GCB‐70) in Overweight Subjects
Authors: BAGCHI DEBASIS , Verma Narsingh , Mittal Madhukar , Swaroop Anand , Bagchi Manashi , Preuss Harry G
Published: November 2023

Obesity is now a worldwide epidemic and a novel natural therapeutic intervention is warranted. We have developed a novel, patent‐pending (PCT/IN2015/000236 dated 10th June 2015), water‐soluble green coffee bean extract, GCB‐70) enriched in 70% total chlorogenic acid including 45% caffeoylquinic acid and <1% caffeine in our laboratories. Our earlier studies demonstrated its novel antioxidant efficacy and its potential efficacy in weight management in rodents. This open‐labelled investigation evaluated the efficacy of GCB‐70 in 100 men and women overweight subjects (age: 18–65 years; body weight: 84.04 ± 1.46 kg) and BMI; 31.45 ± 4.49 kg/m2) over a period of 12 weeks. Institutional Review Board (IRB) and other institutional regulatory approvals were obtained for this study. This study was also registered in www.clinicaltrials.gov NCT02703025 Unique Protocol ID: Protocol #CR‐GCB‐ 70/ 07/14). Capsules (500 mg each, b.d.) were administered by the subjects 30–60 min prior to lunch and dinner. This study examined the body weight, BMI, WC and fasting glucose at 0, 4, 8 and 12 weeks of treatment. HbA1c, plasma leptin levels and thyroid stimulating hormone (TSH) were assessed at 0 and 12 weeks of treatment. Furthermore, extensive blood chemistry, adverse events, and physical health of the subjects were extensively evaluated to demonstrate the broad spectrum safety of GCB‐70. Body weight was reduced by 1.9%, 3.9% and 5.9% in male volunteers at 4, 8 and 12 weeks of treatment, respectively, while under these same conditions approximately 2.3%, 3.8% and 6.0% reductions were observed in female volunteers. BMI was reduced by 1.3%, 3.9% and 5.9% in male volunteers at 4, 8 and 12 weeks of treatment, respectively, while under these same conditions approximately 2.3%, 3.9% and 6.1% reductions were observed in female volunteers. Significant reductions in WC and fasting glucose were observed at these same time points in both male and female volunteers. HbA1c and plasma leptin levels were significantly reduced at 90‐days of treatments as compared to the corresponding baseline values, respectively. Blood chemistry data demonstrated the broad spectrum safety of GCB‐70. Overall, the results demonstrate that GCB‐70 is novel, safe and low caffeine antioxidant supplement effective in healthy weight management.

Support or Funding Information

The Study Was Funded by Cepham Inc, Piscataway, NJ
The Effect Of ‘Catalytic’ Doses Of Fructose And Its Epimers In Acute Single‐Meal Feeding Trials: A Systematic Review And Meta‐Analysis Of Controlled Trials
Authors: Braunstein Catherine Rose , Noronha Jarvis C , Mejia Sonia Blanco , Kahn Tauseef A , Wolever Thomas MS , Josse Robert G , Kendall Cyril WC , Sievenpiper John L
Published: November 2023

Objective

‘Catalytic’ doses (<10g/meal or 36g/day) of fructose and its epimers (allulose, tagatose, and sorbose) may reduce postprandial glycemic responses to carbohydrate loads in people with and without diabetes by inducing glycogen synthesis. To synthesize the evidence of the effects of fructose and its epimers on acute postprandial carbohydrate metabolism, we conducted a systematic review and meta‐analysis of controlled trials.

Methods

We searched Medline, EMBASE, and the Cochrane Library (through Feb 12 2016). We included controlled, single‐meal feeding trials (≥2 hours) investigating the effect of fructose and its epimers (allulose, tagatose, and sorbose) on the postprandial metabolic responses to carbohydrate control meals compared to the same control meals without the sugars. Two independent reviewers extracted all relevant data and assessed risk of bias of individual trials using the Cochrane Risk of Bias Tool. Outcomes included plasma glucose and insulin incremental area‐under‐the‐curve (iAUC). Data were pooled using the generic inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (95% CI). Heterogeneity was assessed by the Cochran Q statistic and quantified by the I2 statistic.

Results

Eligibility criteria were met by 9 controlled feeding trials involving 144 participants in people with and without diabetes. Fructose (5 trial comparisons, MD= −28.65 mmol/L*min [95% CI, −55.36 to −1.93], p=0.04) and allulose (5 trial comparisons, MD= −39.79 mmol/L*min [95% CI, −67.35 to 12.22], p= 0.005) but not tagatose (15 trial comparisons) significantly reduced the postprandial plasma glucose iAUC responses to the carbohydrate control meals. Only allulose significantly reduced the postprandial plasma insulin iAUC to the carbohydrate control meals (MD= −2950.59 pmol/L*min [95% CI, −4844.11 to −1057.06], p=0.002). There was no evidence of heterogeneity in any of the analyses (P>0.1).

Conclusions

Pooled analyses indicate that small doses of fructose and allulose but not tagatose may improve the postprandial glycemic responses to carbohydrate meals without adversely affecting insulin response. There is a need for long‐term randomized controlled trials to assess whether these acute single‐meal effects lead to sustainable benefits in people with and without diabetes.

Protocol registration: clinicaltrials.gov identifier, NCT02776722.

Support or Funding Information

The Tate and Lyle Nutritional Research Fund at the University of Toronto, Canadian Diabetes Association (CDA), Banting & Best Diabetes Centre, and PSI Foundation.
Cyclodextrin‐based nanocarriers for alpha‐tocopheryl phosphate and regulatory activity in THP‐1 monocytes
Authors: Zingg Jean‐Marc , Stamatiou Christina , Daunert Sylvia
Published: November 2023

The vitamin E derivative, alpha‐tocopheryl phosphate (αTP), occurs in small amounts in plasma and animal tissues. Low amounts of αTP are also present in foods but the bioavailability as an intact molecule is very low, since most of it is hydrolyzed. So far no efficient mechanism of intact cellular αTP uptake and tissue distribution has been identified when compared to vitamin E (alpha‐tocopherol, αT). Since αTP has been reported to be more potent in regulating signal transduction and gene expression than αT (e.g. on atherosclerosis, inflammation), a more efficient system to deliver intact αTP to cells in tissues may be useful. Here we characterize the formation of complexes of αTP with the nanocarrier cyclodextrin (CD). αTP/CD formed soluble complexes in a 1 to 2 ratio and generated a homogenous white colloidal emulsion that stayed in homogenous suspension for weeks. The αTP/CD complex inhibited proliferation of THP‐1 monocytes and CaCo2 colon carcinoma cells slightly stronger than αTP. When compared to CD, the complex of αTP/CD extracted cholesterol from cellular membrane of cultured THP‐1 monocytes and HT29 intestinal epithelial cells with higher efficiency and was associated with delivery of αTP to these cells. The αTP/CD complex induced VEGF promoter activity in THP‐1 and HEK293 cells with slightly higher efficiency than αTP. Interestingly, αTP and αTP/CD also reduced the phagocytosis of fluorescent Staphylococcus aureus bioparticles in THP‐1 monocytes/macrophages. αTP/CD assembled to higher order complexes with three types of modified starches and chitosan. These higher complexes had a comparable activity in the above assays and therefore may be useful as protective vehicles for oral, dermal or ocular delivery or as deposit‐enhancer in mucosa for delivery across epithelia.

Support or Funding Information

1R21AI124058‐01
Dose‐effect Relationship between Dietary Iron and Hematological Parameters in Rats
Authors: Yokoi Katsuhiko , Konomi Aki
Published: November 2023

Although the study in iron nutrition has a long history, studies on dose‐effect relationship between dietary iron and hematological parameters are still limited. The aim of this study is to clarify this relationship in rats. Fifty‐four three‐week‐old male Wistar rats were equally and randomly divided into nine groups, and fed for five weeks on graded levels of supplemental dietary ferric citrate: 0, 7, 14, 21, 28, 35 (AIN‐93G formulation), 49, 126, and 252 mg iron/kg. Hematological parameters using blood samples after overnight food withdrawal were measured. Data were analyzed by the Williams or Shirley‐Williams multiple comparison test (if significant heterogeneity of variance existed). Values between dietary iron levels 126 mg/kg and 252 mg/kg were tested by Student's t test. P value less than 0.05 was considered significant. Compared with dietary iron level 126 mg/kg where hemoglobin was highest, hemoglobin, hematocrit, MCV, and MCH were significantly lower at dietary iron level 49 mg/kg and less. Compared with dietary iron level 126 mg/kg, red blood cell counts were significantly lower at dietary iron level 7 mg/kg and less. Compared with dietary iron level 126 mg/kg, reticulocyte counts were significantly increased at dietary iron level 14 mg/kg and less. There were no significant differences in all parameters between dietary iron levels 126 mg/ kg and 252 mg/kg. These results suggest that the breakpoint of dietary iron level for hemoglobin and red cell indices is placed between 49 mg/kg and 126 mg/kg.

Support or Funding Information

This work was supported by Grants‐in‐Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI: no. 25350137).
High‐Density Lipoprotein Cholesterol Concentrations and Particle Size Are Modified by Dietary Zinc in Men
Authors: Shenvi Swapna , Chen Kevin , Kim Elijah , Zyba Sarah , King Sarah , Shigenaga Mark , Killilea David , Holland Tai , Sutherland Barbara , Krauss Ronald , King Janet
Published: November 2023

Objective

To measure biomarkers of lipid metabolism in response to a marginal zinc depletion, repletion, and supplementation in healthy male subjects.

Methods

Eighteen male subjects between ages of 18–45 consumed a controlled diet (80% carbohydrate, 10% fat, 10% protein) with two levels of dietary zinc. Phase I: Low zinc: 6 mg/day with 1.5 mg of phytate (2 weeks); Phase II: Zinc repletion: 10 mg/day with no phytate (4 weeks). Thereafter, a 25 mg/day zinc supplement was administered with an ad libitum diet for 3 weeks (Phase III). Targeted analysis of lipids and lipoprotein particle size were performed using standard methodology.

Results

Plasma zinc levels remained unchanged during Phases I and II in all subjects; they increased by 17.4 ± 3.8% (mean ± SE) at the end of supplementation (phase III). Apo‐A1 decreased significantly from 119.2 ± 13.2 mg/dL (mean ± SD) to 110.2 ± 13.2 mg/dL (p=0.003) at the end of the low zinc period. Apo‐A1 remained low at the end of phase II, but returned back to baseline after supplementation. A similar pattern was observed in HDL‐c and HDL‐L (large buoyant HDL particles) levels across the three phases. Plasma triglyceride levels increased during the 6‐week high‐carbohydrate diet, but were not modified by shifts in dietary zinc. Based on our previous observation of higher DNA strand breaks in the low zinc metabolic period and literature reports linking cancer to low HDL‐c levels, we performed a correlation analysis of DNA strand breaks and HDL subspecies. Our results show that the percent changes in HDL‐L and DNA strand breaks from phase I to II are negatively correlated (r=−0.45; p=0.05).

Conclusion

Results from our studies show that low zinc combined with a high carbohydrate diet increased biomarkers of dyslipidemia, but provision of adequate dietary zinc or a zinc supplement for a short period of time mitigated the increase in these biomarkers.

Support or Funding Information

Harvest Plus
Acceleration of liver regeneration by betaine supplementation after partial hepatectomy
Authors: Jun Doo Sung , Choi Yeo Jin , Ahn Chul Won , Kim Young Chul
Published: November 2023

In living donor liver transplantation (LDLT), stimulation of hepatic regeneration can have tremendous therapeutic relevance for both recipients and donors, however, very few substances have been found capable of stimulating liver regeneration. In this study we examined the effect of betaine, a methyl donor utilized for remethylation of homocysteine to methionine, on liver recovery in rats subjected to two‐thirds partial hepatectomy (PHx). Betaine (1 %) provided either from 2 wk before PHx or after PHx enhanced the growth of liver significantly, reaching a normal liver weight in 7 days after the surgery. Protein expression of cyclin D1 and proliferating cell nuclear antigen (PCNA) was also stimulated by betaine intake. The surgical treatment induced a significant change in hepatic levels of sulfur‐containing amino acids and polyamines. Methionine, S‐adenosylmethionine (SAM), S‐adenosylhomocysteine (SAH), cysteine and taurine were elevated rapidly in the remnant livers after PHx, which was intensified by betaine intake. A drastic increase in hepatic putrescine was noted from 6 h after PHx, while spermidine unchanged and spermine decreased slightly. Betaine administration elevated putrescine and spermidine significantly, but not spermine in the liver. It is suggested that an alteration in the metabolomics of sulfur‐containing substances critically influences the early phase of liver regeneration, probably via modulation of polyamine metabolism. The enhancement of liver recovery by betaine may be attributed to the increase in spermidine levels resulting from an elevation of the SAM availability. This finding raises the possibility that betaine may be effective in promoting the regeneration of liver tissue after damage or transplantation, and therefore, warrants further studies to examine its clinical significance.

Support or Funding Information

Supported by National Research Foundation (NRF) grants (No. 2014‐R1A2A1A11052967 and No. 2009‐0083533) funded by the Ministry of Education, Science and Technology (MEST), Korea.
Glutamine Transporter Expression Profiling in Murine Breast Cancer Reveals Therapeutic Targets for Triple Negative Breast Cancer
Authors: Kron Clare , Bode Barrie
Published: November 2023

Breast cancer is the second most diagnosed cancer worldwide as well as the second leading cause of cancer death in American women. It is estimated that about 40,450 women will die from breast cancer in 2016. Though cancer deaths have been declining since 1989, certain types of breast cancer are more resistant to treatment and have a low survival rate, especially the basal type classified as triple negative. As this category lacks hormone receptors and the human epidermal growth factor receptor 2 (HER2), hormone therapies are ineffective. Basal‐type breast cancers are frequently dependent on glutamine as the major oxidizable substrate for tumor growth, therefore, identification of glutamine transporters and transporter activity is of vital importance in the development of treatment options to either block the uptake of this essential nutrient or to employ its respective transporters for chemotherapeutic drug delivery. The EMT6 cell line, a murine mammary carcinoma from a BALB/c laboratory mouse, has characteristics of triple negative human breast cancer, providing an ideal model for identifying glutamine transporters as it grows equally well in tissue culture and in the genetically identical BALB/c mice. In preparation for implantation of EMT6 in BALB/c mice for tumor establishment and future analysis, studies were done in vitro to determine glutamine dependency, and to compare glutamine transport in EMT6 with the COMMA‐1D cell line, established from normal BALB/c mammary tissue. Results showed that EMT6 is glutamine dependent, and uses several different transporters of glutamine that were differentially expressed in terms of gene expression as well as physiological activity in comparison with COMMA‐1D.
Effective Engagement of Large Numbers of Undergraduate Students in Pharmacology Practicals in Resource‐Poor Settings: A Nigerian Experience
Authors: Kwanashie Helen O. , Olurishe Temidayo O. , Ejiofor Janet I. , Anafi Sherifat B.
Published: November 2023

Conducting undergraduate pharmacology practicals in resource‐poor settings present multi‐factorial challenges including large class sizes, poor staffing and inadequate budget. Typically, a team of 2–4 academic staff, supported by similar number of technical staff, hold such classes 2–3 times a week in a northern Nigeria university department of pharmacology. Modifications to standard practicals have become almost routine, and this paper reports on a technique frequently deployed by the teams to successfully achieve learning objectives with 50 or more students in a practical pharmacology class. The method centres around engaging each and every student in one or more aspects of the processes which form part of the whole practical. Where animals are used, the opportunity is utilised in further transferring practical skills in animal handling as well as theoretical knowledge on the care and use of laboratory animals ‐ including elements of the 3Rs. Standard inputs are pre‐laboratory ‘talks’ by academic staff, in‐class quizzes directed at students, reverse question time, end‐class pooling of results‐cum‐summaries and finally, individual reports submission by students. In part 1 of 2, a dry‐run of an actual practical class will be presented while part 2 will represent sample laboratory results. Such participatory methodologies as described, help to develop independent and team spirits in the students as well as stimulate their interest in pharmacology research.
Evidence for agonist‐specific mechanisms of cannabinoid tolerance.
Authors: Nealon Caitlin , LaFleur Rebecca , Morgan Daniel
Published: November 2023

The focus of this study was to investigate whether G protein‐coupled receptor kinase (GRK)‐ and βarrestin2‐mediated receptor desensitization is required for antinociceptive tolerance to WIN55,212‐2, a synthetic, high potency cannabinoid agonist. We used S426A/S430A mutant mice expressing a desensitization‐resistant form of cannabinoid receptor 1 (CB1) to investigate the essential role of this mechanism in tolerance to WIN55,212‐2. We have previously shown that antinociceptive tolerance to Δ9‐THC is mediated in part by this mechanism, while tolerance to CP55,940, another high potency, synthetic cannabinoid, is only very modestly affected by blockade of this pathway. Antinociceptive tolerance to repeated daily administration of WIN55,212‐2 and CP55,940 was assessed in wild‐type and S426A/S430A mice using the hot plate, tail flick, and formalin tests. We found that antinociceptive tolerance to WIN55,212‐2 was profoundly delayed in the desensitization‐resistant mice compared to wild‐type counterparts. Interestingly, this difference was not observed in tolerance to the hypothermic or cataleptic effects of WIN55,212‐2. We found that antinociceptive tolerance to CP55,940 was slower to develop in wild‐type mice than in mice administered WIN55,212‐2. However, antinociceptive tolerance to CP55,940 was only modestly delayed in desensitization‐resistant mice compared to wild‐type counterparts. These findings suggest that GRK‐ and βarrestin2‐mediated desensitization of CB1 may be the predominant mechanism responsible for antinociceptive tolerance to WIN55,212‐2. This finding suggests the possibility of agonist‐specific mechanisms of tolerance for different cannabinoid agonists.

Support or Funding Information

This research was supported by NIH grant DA036385 and a grant from the Pennsylvania Department of Health using Tobacco CURE funds.
Macrophage COX‐2/mPGES‐1/PGE2 mediates inflammatory pain in peripheral tissues
Authors: Chen Lihong , Yang Guangrui , Grosser Tilo
Published: November 2023

Nonsteroidal anti‐inflammatory drugs (NSAIDs) alleviate inflammatory pain by inhibiting prostanoid formation, but are associated with serious cardiovascular and gastrointestinal adverse effects. Identification of the dominant tissue sources of prostanoid formation may lead to more targeted therapeutic approaches. We studied the contribution of macrophage derived prostanoid formation to inflammatory pain in mice. Selective deletion of COX‐2 in macrophages (Mac‐COX‐2‐KO) by crossing LysMCre mice with COX‐2flox/flox mice resulted in complete suppression of lipopolysaccharide‐induced prostaglandin (PG) E2, prostacyclin and thromboxane in peritoneal macrophages. Mac‐COX‐2‐KO mice exhibited normal mechanical and heat sensitivity at baseline, as well as normal formalin induced chemical pain, while both mechanical and thermal hyperalgesia were significantly reduced in complete Freund's adjuvant (CFA) evoked hind paw inflammation. Inflammatory cell infiltration and concentrations of PGE2, IL‐1β and TNFα were significantly reduced in Mac‐COX‐2‐KO paw tissues following CFA induction. This was reflected by a reduction in paw swelling. Mechanical and thermal pain hypersensitivity were also reduced in the zymosan‐evoked monoarticular arthritis and collagen II antibody‐induced polyarthritis. We identified PGE2 as the major prostanoid which underlies the effect of macrophage COX‐2 on hyperalgesia using macrophage mPGES‐1 deficient mice obtained by crossing mPGES‐1flox/flox with LysMCre mice (Mac‐mPGES‐1‐KO). These mice fully recapitulated the phenotypes observed with Mac‐COX‐2‐KO. Pretreatment of Mac‐mPGES‐1‐KO mice with celecoxib at a biochemically‐validated COX‐2 selective concentration (100mg/kg/day) failed to reduce CFA‐induced inflammation and hyperalgesia beyond deletion of mPGES‐1 in macrophages, further demonstrating the importance of macrophage‐derived PGE2. This also indicates that central COX‐2 plays only a minor role in this setting. Our results demonstrated that the macrophage COX‐2‐mPGES‐1‐PGE2 biosynthetic pathway might be the dominant source of prostanoids in inflammatory pain hypersensitivity in peripheral tissues and may afford a more targeted approach to NSAID therapy.

Support or Funding Information

American Heart Association Scientist Development Grant: 15SDG22780013
Study of Daily Genistein Ingestion on Spatial Memory and Olfaction in Triple Transgenic Alzheimer's Mice
Authors: LeBlanc Hayley Rachel , Williamson Alyson Caye , Wrenn Craige Charles
Published: November 2023

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by the accumulation of beta amyloid plaques and the formation of neurofibrillary tau tangles. These plaques and tangles lead to the learning and memory deficits characteristic of AD. Estrogen and estrogen‐like compounds have been shown to slow the development of plaques and tangles. Though estrogen receptors are found in the male hippocampus, it is unclear how estrogen affects learning and memory in the male hippocampus. Male triple‐transgenic (3×Tg‐AD) mice mimic the pathology and learning and memory deficits of AD in humans. To examine the potential effects on the male hippocampus, 3×Tg‐AD mice were either fed a dose of 4–5 mg/kg of genistein, a phytoestrogen found in soy or a placebo and tested behaviorally in the Morris Water Maze and Olfactory Habituation‐Dishabituation tasks. The 3×Tg‐AD mice had significantly longer swim paths to find a hidden platform as well as a lack of selective search in the platform location when the platform was removed. There was no significant difference between the 3×Tg‐AD and wild type mice during the olfactory task of habituation‐dishabituation. As the pathology of the AD develops in the 3×Tg‐AD mice, the mice will be retested to examine the differences in learning and memory. Presently, the 3×Tg‐AD were impaired in successfully learning the location of a hidden platform but were not impaired in their olfactory abilities.

Support or Funding Information

Ronald Troyer Research Fellowship, Drake University

Harris Research Endowment, Drake University

Drake Undergraduate Science Collaborative Institute, Drake University
Stroke protection via stimulation of fatty acid oxidation increases astrocyte spare respiratory capacity
Authors: Sifuentes Mikaela , Lechleiter James
Published: November 2023

Stroke is a growing threat among the aging population in the United States, yet few treatments exist for afflicted patients. Research in our lab identified the stimulation of astrocyte mitochondrial metabolism as a protective strategy against stroke. Thyroid hormone has been observed to reduce stroke lesion size, a treatment that we hypothesize is mediated by stimulating fatty acid oxidation (FAO) via the mitochondrial trifunctional protein (MTP). We observe that treatment with the active form of thyroid hormone (T3) protects the mouse brain from stroke in a mechanism requiring astrocyte metabolism and the presence of brain MTP. T3 stimulates an increase in maximal respiration and spare respiratory capacity in a dose‐dependent manner, which is blocked by inhibition of FAO. We also report that T3 increases astrocyte viability and reduces the formation of starvation‐induced lipid droplet formation, suggesting that T3 directly increases astrocyte resistance to conditions of nutrient‐deprivation, such as that observed in stroke. Altogether, our data indicate that thyroid hormone protects the brain against stroke by increasing astrocyte survival in a FAO‐dependent mechanism.

Support or Funding Information

Research supported by National Institutes of Health R01AG007218 and the American Heart Association Predoctoral Fellowship 16PRE27670002