bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinoic Acid Synergizes with Insulin to Induce Glucose Disposal in L6 Rat Skeletal Muscle Cells
Authors: Goff Matthew , Chen Guoxun
Published: June 2021

Skeletal muscle is the largest body mass for glucose uptake and usage. Alterations of muscle cell number, differentiation, and function can affect glucose homeostasis in the body. As an essential micronutrient, vitamin A plays a critical role in a variety of physiological functions including glucose and lipid metabolism. However, its role in muscle glucose metabolism has not been well established. Therefore, our goal was to investigate the effects of retinoic acid (RA) on glucose usage in rat L6 muscle cell line, a well‐known model for skeletal muscle cell differentiation and metabolism. L6 cells were maintained in DMEM with 10% FBS until ~100% confluence and induced differentiation in medium containing 2% horse serum (HS). The differentiated cells were treated with increasing dosages of RA (0.3, 1, 3, and 10mM) for a period of 6 days. Media were collected every 2 days for the measurements of pH and remaining glucose levels. Compared to cells in the 2% HS control groups, cells treated with 1, 3, and 10mM RA displayed significant decreases in glucose levels at 6 day. Insulin treatments (1 to 100nM) significantly decreased medium glucose levels after 2 days. When RA (1mM) and insulin (0.1nM) were added together, a further decrease of media glucose levels was observed at day 4. At day 4, treatment of 0.1nM insulin alone did not cause a significant decrease in glucose when compared to the control. Therefore, we conclude that RA and insulin signaling pathways work cooperatively to enhance muscle cell glucose utilization.
The Effects of Potatoes and other Carbohydrate Side Dishes on Meal Time Food Intake, Blood Glucose and Satiety Response in Lean Healthy Children
Authors: Akilen Rajaduai , Deljoomanesh Neshat , Al‐Dabous Khulood , Arshad Muhammad , Smith Chris , Hamilton Jill , Anderson Harvey
Published: June 2021

Background

The effect of carbohydrate foods on blood glucose is ranked by their glycemic index. Boiled‐mashed‐potatoes (BMP) are ranked as high GI but pasta and rice have moderate GI ranking.

Objectives

To compare ad libitum consumption of common carbohydrate dishes on meal‐time satiety, food‐intake blood glucose and insulin in 11 to 13 year normal weight children.

Methods

Two studies were conducted. At weekly intervals, children (experiment‐1: 12M, 8F; experiment‐2: 6M, 3F) randomly received 1 of 5 ad libitum carbohydrate meals of rice, pasta, BMP, fried‐french‐fries (FFF) or baked‐french‐fries (BFF) together with 100g lean beef as a lunch time meal. In experiment‐1, food intake over 30 minutes and subjective appetite was measured for120 minutes. In experiment‐2, the same outcomes were measured along with blood glucose and plasma insulin.

Results

The results for both boys and girls were pooled as sex was not a factor(P=0.51). In both experiments, children consumed the 30% less calories at meals with BMP(P<0.0001) compared to all other treatments, which were similar. Expressed as a change in appetite per kilocalorie, BMP lowered appetite more than all other treatments(P<0.0001). In experiment‐2, FFF resulted in the lowest(P<0.0001) end of meal glucose and insulin concentrations at 30 min.

Conclusion

The role of carbohydrate foods consumed ad libitum at meal time on food intake, appetite, blood glucose and insulin responses in children is not predicted by the GI.
Patterns of Self‐Reported Dieting and Energy Intake in 15y Girls
Authors: Balantekin Katherine , Birch Leann , Savage Jennifer
Published: June 2021

Dieters use various combinations of weight control behaviors, which may differentially influence energy intake. Objectives were to use Latent Class Analysis (LCA) to identify and predict patterns of weight control behaviors and to examine group differences in energy intake. Subjects were 167 15y girls. Weight control behaviors were assessed using the French Weight Control Scale. BMI, restraint, weight concerns, and dieting frequency were assessed as predictors. Both self‐reported (3 24h dietary recalls, used to categorize reporting accuracy) and weighed intake (EAH protocol, standardized lunch) assessed energy intake. LCA identified four classes of weight control behaviors, Non‐dieters (26%; no behaviors), and three dieting groups: Lifestyle (16%; use of exercise and increased fruits/vegetables), Dietary Guidelines (43%; decreased overall intake and energy density), and Extreme (17%; reported all behaviors). BMI, restraint, weight concerns, and dieting frequency increased on an ordinal scale across groups, from Non‐dieters to Extreme dieters. Self‐reported, EAH, and lunch intakes differed by group (p < 0.05). Girls in the Extreme group were more likely to be classified as under‐reporters, and had the lowest self‐reported intake, but ate significantly more during controlled feeding protocols in the laboratory. Three patterns of self‐reported “dieting” were identified, increasing in the number and severity of weight control behaviors used and distinct in descriptive characteristics. Patterns of intake in the laboratory support the view that the lower energy intake reported by Extreme dieters is likely due to under reporting as an intent to decrease intake, not actual decreased intake.
Sulfidogenic Bacteria Abundance in Colonic Mucosa is Positively Correlated with Milk and Animal Fat Intake and Negatively Correlated with Mono and Polyunsaturated Fatty Acids
Authors: Wolf Patricia , Cummings Peter , Shah Natasha , Gaskins H Rex , Mutlu Ece
Published: June 2021

Correlations between mucosal sulfidogenic bacteria and diet were examined using sigmoid biopsies and the NIH Dietary History Questionnaire collected from 9 healthy subjects over 4 time points (0, 3, 6, and 9 months). Bacterial genera, namely Akkermansia muciniphilia, Bilophila wadsworthia, Desulfovibrio spp. (DSV), Desulfobulbus spp. (DBB), Desulfobacter spp. (DSB), and Desulfotomaculum spp. (DFM) were quantified by 16S rRNA gene‐specific qPCR. Functional genes for pan‐dissimilatory sulfite reductase (dsrA) and B. wadsworthia specific dsrA (dsrA‐BW) were measured along with three genes utilized for cysteine fermentation by Fusobacterium nucleatum: L‐cysteine desulfhydrase (Lcd), L‐methionine‐γ‐lyase (FN1419), and cystathionine‐β‐synthase (FN1055). Significant positive correlations were observed between high saturated fat intake and increased abundance of DSB, dsrA‐BW, and A. muciniphilia; specifically those present in milk fat, palm, and coconut oils. Similarly, DSB abundance was increased with total dairy intake, (r = 0.48 p = 0.003). In addition, DSV was positively associated with red meat (r = 0.36 p = 0.04) and cholesterol (r = 0.30 p = 0.02) intakes. Conversely, DSB was negatively associated with intake of mono and polyunsaturated fatty acids, particularly linoleic (r = ‐0.46 p = 0.0059), erucic (r = ‐0.52 p = 0.002), eicosenoic (r = ‐0.56 p = 0.0006), and docosahexaenoic (r = ‐0.45 p = 0.007) acids. Collectively, these observations demonstrate mucosal sulfidogenic bacteria abundance is positively correlated with high milk and animal fat intake and negatively correlated with mono and polyunsaturated fatty acids.
The intake of ready to eat cereals in breakfast is associated with fewer intakes of 24 h unsaturated fats but not of fruits, vegetables or fiber in Mexican children
Authors: Contreras Alejandra , De La Cruz Vanessa , Villalpando Salvador
Published: June 2021

Introduction

The consumption of Ready to eat cereal (RTEC) at breakfast has been associated with a better dietary habits and healthy life styles.

Objective

To describe the macronutrient intake, food consumed with breakfast and healthy lifestyles in Mexican children by category of RTEC: Breakfast RTEC, Non‐RTEC breakfast and breakfast skippers (BS).

Methods

Dietary data were collected from a 24h recall. We examined fruits and vegetables, fiber, saturated and unsaturated fat intakes, screen time, and physical activity. Statistical analyses were adjusted by the survey design.

Results

Preschoolers (11.5%), scholars (10.2%) and adolescents (5.7%) had RTEC breakfast. The foods most frequently consumed with RTEC were milk sugar and fruit. No differences between adequacy of fruits, vegetable and fiber were found by RTEC categories. The 24 h intake of saturated (20.5g vs 17.8g, p<0.05) or unsaturated fats (28.3 vs 23.9 g, p<0.05) was greater in preschoolers breakfasting non‐RTEC than those eating RTEC or non‐breakfast. The 24h intakes of unsaturated fats was lower in scholar girls (35.5 g vs 39.3 g & 41.8g, p<0.05) and adolescents (40.0g vs 45.5g, & 52.0g respectively, p<0.05) RTEC consumers thannon‐RTEC or BS individuals. Adolescents that had breakfastcomparedwith non‐RTEC or BS individuals had the same physical activity and less screen time.

Conclusion

The RTEC intake is associated with fewer intakes of 24 h fat intakes, without differences in the intake of fruits, vegetables, fiber, physical activity and screen time.
Pinolenic Acid Downregulates Anabolic Pathway of Lipid Metabolism in HepG2 Cells
Authors: Lee Ah Ron , Han Sung Nim
Published: June 2021

Pine nut oil has been reported to attenuate hepatic triglyceride accumulation. However, effect of pinolenic acid (18:3, all‐cis‐Δ5,9,12), a unique component of pine nut oil, on hepatic lipid metabolism has not been studied. We investigated whether pinolenic acid affects lipid metabolism using HepG2 human liver cell line. HepG2 were incubated in serum‐free medium supplemented with 50 μM BSA (control), palmitic, oleic, γ‐linolenic, pinolenic, or α‐linolenic acids or EPA for 24h. Lipid accumulation was determined by Oil red O staining. mRNA levels of genes related to lipid synthesis (Srebf‐1c, Fasn, SCD1, ACC1), lipid oxidation (ACC2, Ppara, Cpt1), lipoprotein infusion (LDLr), and genes that may be involved in downregulation of lipogenic pathway (ACSL3, ACSL4, ACSL5) were determined by qPCR. ACSL4 protein level was measured by Western blot. mRNA levels of Srebf‐1c, Fasn, and SCD1 were significantly decreased in pinolenic acid group compared to control group (53%, 54%, and 38% less). Pinolenic acid also significantly reduced gene expression level of LDLr (43% less). ACSL3 mRNA level was significantly decreased (30% less) and ACSL4 mRNA level tended to be decreased in pinolenic acid group (20% less, P=0.082) relative to control group. In conclusion, pinolenic acid downregulated lipid anabolic pathway in hepatocyte by reducing markers related to lipid synthesis, lipoprotein infusion and regulation of lipogenic pathway. Supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (grant number NRF‐2010‐0024878).
The Effect of Breakfast Protein Source on Postprandial Hunger and Glucose Response in Women
Authors: Crowder Christina , Neumann Brianna , Johnson Dallas , Baum Jamie
Published: June 2021

Currently, there is debate as to what the macronutrient composition of breakfast should be for optimal health. Studies have shown that subjects who eat a breakfast high in protein (PRO) stay fuller throughout day compared to subjects who consumed a carbohydrate (CHO)‐based breakfast. The objective of this study was to determine if protein quality (animal v plant) at breakfast makes a difference in postprandial (pp) satiety and glucose response when compared to a standard CHO‐based breakfast. Normal weight women (n=7) ages 18‐36 were provided 3 isocaloric breakfasts: animal PRO (30% PRO, 40% CHO, 30% fat), plant PRO (30% PRO, 45% CHO, 30% fat), and CHO‐based (20% PRO, 50% CHO, 30% fat). Breakfasts were consumed in a randomized, crossover design with at least a 1‐week washout period between each breakfast. Satiety and glucose measurements were taken at 0, 15, 30, 45, 60, 90, 120‐min postprandial. Subjects preferred (P < 0.05) the taste and appearance of the animal PRO over the plant PRO and CHO‐based breakfasts and the plant PRO was preferred (P < 0.05) to the CHO‐based breakfast. There was no significant difference in satiety response to the 3 breakfasts over the 2‐hour pp period. In addition, there was no significant difference in glucose response over the 2‐hour pp period. However, subjects had a lower peak in pp glucose at 30 min after consuming animal PRO (36.2%) compared to plant PRO (44%) and CHO‐based (47.8%). Although there is no difference in satiety response, these data suggest that consumption of an animal PRO breakfast results in a lower pp glucose response. Funded by University of Arkansas Honors Grant.
Nopal consumption attenuates biochemical abnormalities and microbiota disbiosis in a diet induced obesity (DIO) model
Authors: Sanchez‐Tapia Monica , Tovar Armando , Torres Nimbe
Published: June 2021

Nopal is a cactus considered as functional food due to its nutritional value and beneficial effects on health. However, it is not known whether the oligosaccharides of nopal have prebiotic activity. The aim of this study was to investigate the effect of consumption of nopal on intestinal microbiota in a model of DIO. Wistar rats were fed control diet (AIN‐93) or a high fat diet +5% sucrose in the drinking water (HFD+S) for 7 mo. Rats fed the HFD+S increased body weight and showed glucose intolerance and metabolic inflexibility. Also, there was a significant disbiosis in the intestinal microbiota. There was a decrease in Bacteroidetes Lacobacillus, Actinobacteria, Bifidobacteria, Akkermancia and B. thetaiotaomicron, and an increase in Firmicutes. Obese rats were then divided into 4 groups fed one of the following diets 1) AIN‐93, 2) AIN‐93 + 5% nopal, 3) HFD + 5% S and 4) HFD + 5% S + 5% nopal for a mo. The addition of nopal in the diet decreased body weight gain, improved glucose tolerance and metabolic inflexibility, and biochemical parameters, decreased the expression of SREBP‐1 involved in lipogenesis and increased PPAR‐α involved in fatty acid oxidation. Finally the inclusion of nopal in the HFD+5%S restored the intestinal microbiota by increasing the Bacteroidetes, Lactobacillus, Akkermancia, Bifidobacterium along with a decrease in Firmicutes. Therefore, the results suggest that bioactive compounds of nopal may have beneficial effects on obesity control as well as a prebiotic effect.

Supported by Instituto Danone de Mexico
Preterm Infant Gut Microbiome and Weight at 36 Weeks Corrected Gestational Age
Authors: Taft Diana , Ward D , Ollberding N , Schibler K , Ambalavanan N , Yu Z , Newburg D , Davidson B , Morrow A
Published: June 2021

The gut microbiota is thought to influence obesity, but the impact of the microbiota on preterm infant growth has not been studied. We hypothesized that growth of preterm infants could be associated with the microbial community. We therefore analyzed 75 preterm infants born at <29 weeks gestational age (GA) who survived free of necrotizing enterocolitis and sepsis until hospital discharge. We collected stool samples at week 3 of life and extracted DNA to sequence the 16s rRNA gene using Illumina MiSeq. Weight, length, and head circumference were measured at birth and at 36 weeks corrected GA. Size percentile by GA was calculated using the 2013 Fenton growth chart. Using weighted UniFrac, ordination, and ordisurf in QIIME and R, we tested for an association between the gut microbiome and size at 36 weeks corrected GA. Size variables were categorized by a median split and screened for association with the microbial community using the Linear discriminant analysis Effect Size (LEfSe) method. Regression modeling was used to confirm LEfSe findings. Weight percentile at 36 weeks corrected GA was significantly correlated with gut microbiome and with higher relative abundance of Proteobacteria at week 3 of life. The association between weight and Proteobacteria remained significant after including potential confounding factors in the regression model. In conclusion, the composition of the preterm infant gut microbiome correlates with infant weight percentile at 36 weeks corrected GA.
MD2 may mediate free fatty acid‐induced inflammation and insulin resistance
Authors: Fang Qilu , Pan Yong , Liang Guang
Published: June 2021

Background

Insulin resistance is a major metabolic abnormality of patients with obesity. Free fatty acid (FFA), whose circulating levels are often increased in obesity, causes chronic low‐grade inflammatory state that plays an important role in the development of insulin resistance. Myeloid differentiation 2 (MD2) is an assistant protein of TLR4 and plays a critical role in LPS‐induced acute inflammation. Although several reports have shown that FFA induces chronic inflammation via TLR4 signaling, it is unknown if MD2 was required in this progress.

Method

Liver HL7702 cells exposed to palmitic acid (PA) were used for in vitro studies. Apoe‐/‐ mice fed with high‐fat diet and orally administrated with specific MD2 inhibitors were used. In addition, C57/BL6 mice and MD2‐knockout C57/BL6 mice were i.v. injected with PA twice a day for one week to investigate the role of MD2 in PA‐induced acute insulin resistance model.

Results

In HL7702 cells, PA obviously induced the release of inflammatory cytokines via activation of JNK and IKKβ, and subsequent insulin resistance as evidenced by the decrease in phosphorylation of IRS1 Tyr and AKT. However, either pharmacological inhibition by two previously found small molecule inhibitors L6H21 and L6H9 or genetic silencing by MD2 siRNA significantly reversed these pathological effects induced by PA. Then, we found both oral administration with L6H21 or L6H9 in Apoe‐/‐ mice significantly attenuated the in vivo inflammation and insulin resistance. More importantly, MD2 knockout mice showed obvious tolerance in response to PA injection.

Conclusion

MD2 mediates PA‐induced inflammatory and subsequently insulin resistance, and MD2 may be a potential therapeutic target on obesity and insulin resistance.
Elevated Irisin Expression in NASH Livers
Authors: Nugent Colleen , Baker Susan , Liu Wensheng , Mastrandrea Lucy , Baker Robert , Zhu Lixin
Published: June 2021

Background

Data mining with our microarray database suggested that irisin is one of the most highly elevated genes in livers of non‐alcoholic steatohepatitis (NASH). NASH is the severe form of non‐alcoholic fatty liver disease (NAFLD) and is characterized by hepatic steatosis, inflammation and fibrosis. Irisin, an adipomyokine implicated in the initiation of a browning effect of adipose that may profoundly affect the metabolic status of NASH patients. Our microarray analysis suggested elevated liver irisin and chemokine ligand 14 (CXCL14). CXCL14 is a chemokine that participates in glucose metabolism and inflammation. We therefore tested the hypothesis that inflammation is a trigger for hepatic irisin expression.

Methods

Biopsy‐proven adolescent NASH patients were compared to controls from healthy livers from donors of similar age and gender. Irisin gene expression was evaluated by microarray and quantitative real‐time PCR.

Results

Hepatic irisin gene expression was increased in NASH compared to controls. Microarray data showed NASH/Normal = 30.49

(p = 0.0008) and CXCL14/Normal = 108.34 (p = 0.0005). qRT‐PCR showed elevated irisin (p =0.0001) and CXCL14 (p=0.0009) expression. Significant correlations were noted between irisin message and hepatic inflammation grade (r = ‐ 0.65, p = 0.0008) but not the pathologic scores for fibrosis or steatosis.

Conclusions

This study indicates that irisin gene expression is induced in NASH. Irisin expression correlates with CXCL14, a representative inflammatory chemokine. These observations suggest that irisin may be playing a role in the mechanism of inflammation.
Statistical Modeling Approaches with Taste Functioning and Central Adiposity in Women: Implications for Mining the New National Health and Nutrition Examination Survey (NHANES) Taste and Smell Protocol
Authors: Rawal Shristi , Huedo‐Medina Tania , Hoffman Howard , Duffy Valerie
Published: June 2021

For the first time, taste functioning is assessed in NHANES 2013‐2014 with measures that capture genetic and environmentally‐mediated variation in taste, previously shown to associate with diet behaviors and adiposity. Mining an existing database of 407 ostensibly healthy women (35±17 years), we utilized structural equation modeling to test paths of association between self‐reported risk factors for taste alteration (otitis media, head trauma, tonsillectomy), NHANES taste measures (intensities of concentrated NaCl and quinine on the tongue tip and whole mouth) and central adiposity. Thirty‐nine% were overweight/obese; 21% had elevated waist circumference (WC). Diminished taste intensity on the tongue‐tip, measured directly or as ratio to whole mouth intensity, was explained by taste risk factors and associated with greater WC. Greater WC also was explained directly by age, lower papillae density (another marker of taste variation) and taste risk factors. Additionally, tongue tip‐whole mouth ratio partially mediated (indirect effect, β=‐0.03, p <0.05) the association between head trauma and WC. The model showed good fit indices, explaining 15.7% variance in WC. The model excluding papillae density showed similar results. In summary, NHANES taste measures can have relevance to nutrition‐related health outcomes with paths of association between risk factors for taste alteration, taste functioning and adiposity. Our findings provide a framework for analyzing NHANES taste data to study associations between taste, dietary behaviors and health (Supported by NIDCD).
Effect of Defatted Pepper Seed Extracts on High‐fat Diet‐induced Obesity in Mice
Authors: Sung Jeehye , Lee Junsoo
Published: June 2021

Obesity is one of the most common metabolic syndromes and poses a major worldwide threat to human health. Recently, natural agents that may be beneficial for improving obesity have received increasing attention. In this study, we investigate the antiobesity effect of defatted pepper seed extracts (DPSE) in diet‐induced obese mice. Male C57BL/6J mice were fed a normal diet (ND) or high fat diet (HFD) with or without DPSE (10, 50 and 100 mg/kg body weight) for 7 weeks. Body weight and food efficiency ratio of mice fed HFD plus DPSE were dose‐dependently decreased compared to those in HFD. Epididymal adipose tissue and liver weights were significantly lowered in mice fed HFD plus DPSE compared to those in HFD. DPSE also lowered triglyceride and cholesterol concentration in plasma. Moreover, DPSE also significantly reversed the HFD‐induced elevation of the expression of the key adipocyte differentiation regulator in the adipose tissue. Furthermore, DPSE resulted in increased phosphorylation of AMP‐activated protein kinase (AMPK) and acetyl‐CoA carboxylase (ACC) in the liver. These results suggest that DPSE may have excellent hypolipidemic potential to prevent obesity.
Lutein Accretion Corresponds to Activity of Metabolic Pathways during Brain Development
Authors: Lieblein‐Boff Jacqueline , Johnson Elizabeth , Kennedy Adam , Lai Chron‐Si , Kuchan Matthew
Published: June 2021

Lutein is well known for its role as an antioxidant in the macula of the eye, and recent reports suggest that lutein may be important for other areas of the brain as well. For instance, lutein is correlated with cognition scores in older adults, and lutein was found throughout the infant brain in areas important for learning and memory. We hypothesize that lutein has importance beyond its role as an antioxidant in the developing brain. The objective of this study was to better understand the role of lutein in the infant brain. To accomplish this task, we performed post‐mortem metabolomic analyses of human infant brain tissues from three regions important for learning and memory, including the frontal cortex, hippocampus, and occipital cortex. Metabolomic profiles were compared to lutein concentration in each sample, and those metabolites that correlated to lutein concentrations in these brain regions were identified and reported here. We found that lutein positively correlated with metabolites of lipid pathways, amino acid neurotransmitters, as well as the antioxidant homocarnosine. Furthermore, these correlations were independent of infant age and were often brain region specific. Revealing connections between lutein and metabolic pathways will hopefully shed light on other important roles of lutein in the human brain during development. This study was funded by Abbott Nutrition.
Tissue Bioavailability of Tart Cherry Anthocyanins
Authors: Kirakosyan Ara , Seymour E Mitchell , Kaufman Peter , Bolling Steven
Published: June 2021

The therapeutic effects of tart cherry anthocyanins cannot be understood without analysis of their tissue distribution,metabolism, and excretion. The definition of bioavailability simply refers to the proportion of known compound that is absorbed and metabolised in an organism. Tissue uptake of anthocyanins may depend on their chemical structure, as influenced by the nature of the attached sugar moiety, and also, by the structure of the aglycone. The parent phytochemicals contain functional groups (e.g., a hydroxyl group) that often undergo conjugation reactions with endogenous compounds to yield more polar and water‐soluble compounds. The latter are usually ideal substrates for active transport out of cells, tissues, and organs with eventual excretion from the body. The sugar conjugates of anthocyanins may also have an effect on the bioavailability of bioactive phytochemicals. Consequently, it is not only important to know how much of a bioactive metabolite is present in tart cherry; but it is even more important to know how much of that present is bioavailable. In the present study, we show that intake of tart cherry is associated with anthocyanin appearance in several tissues of healthy rats. This information affects hypotheses of the molecular mechanisms of bioactive compounds at target sites and how they vary among tissues. While the current work focuses on anthocyanin tissue bioavailability, results may be impacted by the complex polypharmacy of bioavailable tart cherry phytochemicals and their varied sugar moieties that affect absorption, distribution, metabolism, and excretion.

Acknowledgements: This study was supported by an unrestricted grant provided by The Cherry Marketing Institute, MI, USA.
Dietary Fat Composition Effects on Postprandial Systemic Markers of Inflammation and Metabolism
Authors: Lyte Joshua , Hollis James , Gabler Nick
Published: June 2021

Dietary fat is a potential mediator of metabolic disease although the mechanisms responsible have yet to be fully elucidated. n‐3 polyunsaturated fatty acids may reduce the risk of developing metabolic disease by attenuating postprandial endotoxemia and inflammation. The objective of this study was to determine if a meal's fatty acids composition influenced postprandial serum and plasma markers of inflammation. We hypothesize that consuming meals containing n‐3 fatty acids will reduce systemic markers of postprandial inflammation compared to meals enriched in n‐6 or saturated fatty acids. Adult participants (n=31) were required to report to the lab on four separate occasions. Then, an indwelling catheter was inserted and a baseline blood draw collected. Participants then ate one of the four test meals that provided 1) 20% fat or 35% fat with 2) n‐3 3) n‐6 or 4) saturated fat. Pre‐ and postprandial blood samples were collected over a 5 hour period. Serum and plasma were analyzed for metabolites and biomarkers of acute systemic inflammation and endotoxin. Data was analyzed using repeated‐measures ANOVA. There was no statistically significant effect of meal fat content on serum concentration of triglyceride, C‐reactive protein or other metabolites (p < 0.05). Differences in the fat composition of a meal did not influence postprandial concentrations of the measured markers of inflammation. Ongoing evaluation of samples to determine endotoxin content will examine a potential role for fatty acids in modulating postprandial endotoxemia.
Piperlongumine Enhances Chemotherapy‐Induced Pancreatic Cancer Cell Death
Authors: Dhillon Harsharan , Reindl Katie
Published: June 2021

Pancreatic cancer is one of the most deadly cancers with a nearly 95% mortality rate. The large majority of pancreatic cancer patients have mutations in the K‐ras oncogene which contribute to uncontrolled cell proliferation. The poor response of K‐ras mutant tumors to currently available chemotherapy and the extremely low survival rate of pancreatic cancer patients point to a critical need for alternative therapeutic strategies. The use of reactive oxygen species (ROS)‐inducing agents has emerged as an innovative and effective strategy to treat K‐ras mutant cancers. We investigated the effects of a known ROS inducer, piperlongumine (PPLGM), a bioactive agent found in long peppers, alone and in combination with chemotherapeutic agents (gemcitabine and erlotinib) on pancreatic cancer cell viability, survival, and apoptosis. MIA PaCa‐2, PANC‐1 (K‐ras mutant), and BxPC‐3 (wild‐type K‐ras) cells were treated with PPLGM, erlotinib, gemcitabine, and their combinations. Cell survival and apoptosis were assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT), clonogenic survival, and histone‐DNA ELISA assays. The combination of PPLGM, erlotinib, and gemcitabine resulted in a greater reduction in cell viability and induction of apoptosis in all three pancreatic cancer cell lines when compared to any agent alone. These results suggest that the use of PPLGM in combination with chemotherapeutic agents could be a successful strategy for achieving better treatment outcomes in K‐ras mutant pancreatic cancer patients.
QUERCETIN IMPACTS ETC/OXPHOS ACTIVITIES IN ISOLATED HEPATIC MITOCHONDRIA OF MICE
Authors: Guo Xin , Wu Lei , Clarke Stephen , Lin Dingbo
Published: June 2021

Objective

In general, quercetin attenuates oxidative stress and enhances mitochondrial biogenesis in the development of obesity and/or diabetes. In this study we wished to determine how quercetin impacted the mitochondrial function by examining mitochondrial electron transport chain/oxidative phosphorylation (ETC/OXPHOS) in isolated mouse hepatic mitochondria.

Methods

Male wild type 129 S6 (WT) mice, at 6 weeks of age, were used. Isolated hepatic mitochondria were treated with quercetin (0, 2.5, 5, 10, and/or 20 μM) for 15 min. Then the individual ETC complex activity, basal oxygen consumption, maximum ATP utilization, maximum respiratory capacity, and proton leak were measured via assays of electron flow and coupling.

Results

Quercetin decreased the basal respiratory rate and the maximum respiratory capacity. No change was observed in maximum ATP utilization, proton leak, and activities of ETC complex I, II and III. However, quercetin at a low dose (e.g., 2.5 μM) significantly increased the ETC complex IV activity. The effect was then diminished dose dependently.

Conclusions

Quercetin may lower the mitochondrial respiratory activity through mediating the ETC complex IV.
Cranberry Phenolic Compounds Decrease Fat Accumulation in Caenorhabditis elegans
Authors: Sun Quancai , Shen Peiyi , Yang Jeremy , Park Yeonhwa
Published: June 2021

Cranberries are rich source of phenolic compounds (i.e. phenolic acids, flavonoids, anthocyanidins) and have been linked to many health benefits. A recent report suggested that cranberry bioactives inhibit adipogenesis in 3T3‐L1 cells. Thus, we investigated the mechanisms of cranberry bioactives on lipid metabolism using Caenorhabditis elegans model. We evaluated the effects of cranberry water soluble compounds (contains approximately 6.6% phenolic acids, 2.2% flavonoids and 0.6% anthocyanidins) on fat accumulation, pumping rate (food intake), and locomotive activity in wild type (N2). The effect of water‐soluble cranberry compounds on fat accumulation in deficiency strains, sbp‐1 (ep79), aak‐2 (ok524), daf‐16 (mgDf50), and nhr‐49 (ok2165) (which represent SREBP‐1, AMPKα, FOXO3a, and PPARα respectively in mammal) were also investigated. In wild type (N2), no difference in pumping rates or locomotive activities after treating with cranberry bioactives were observed, suggesting no influence on food intake or activity. Treatment with cranberry extract (0.004 and 0.016 mg/ml Gallic acid equivalent) dose‐dependently reduced overall fat accumulation in wild type (N2), 43% and 74% reduction compared to control, respectively. Treatment of cranberry extract decreased fat accumulation in aak‐2 mutants, but only minimal effects were observed in sbp‐1, daf‐16 and nhr‐49 strains. We further confirmed that cranberry bioactives down‐regulated sbp‐1 expression as observed in transgenic strain CE548 {epEx141 [sbp‐1::GFP::SBP‐1]}. These data suggest that water‐soluble cranberry phenolic compounds effectively reduce fat accumulation, are dependent on sbp‐1, daf‐16 and nhr‐49, but not aak‐2.
Synergistic Effects of Phenolic Mixtures in Human Cell Models of Aging
Authors: Fisher Laurel , Ianiro Teodoro , Lau Francis , Wang Hong , Daggy Bruce
Published: June 2021

The health benefits associated with fruit and vegetable consumption are attributed, in the main, to fiber and micronutrients and recent research has focused on the role of phenolics (polyphenols) in mediating healthful dietary effects. While most plants contain complex mixtures of polyphenols, isolated compounds, such as resveratrol, have been widely studied and shown to influence the activity of multiple cellular metabolic and signaling pathways. Indeed, based on its actions on several cellular regulatory systems, resveratrol has been proposed to be the active molecule underlying the benefits of grape and red wine consumption. To test the hypothesis that phenolic mixtures containing resveratrol produce variable and non‐additive effects versus resveratrol alone, their antioxidant capacity (ORAC) and their effects in several in vitro models of cellular aging were compared using identical concentrations (µg phenolics/ml). Compared to resveratrol alone, the same concentration of a mixture of muscadine grape polyphenols plus resveratrol produced synergistic effects on ORAClipophilic but not ORAChydrophilic. Likewise, the phenolic mixture exhibited 10X greater potency versus resveratrol in inhibiting protein glycation. Non‐additive/synergistic effects (p<0.01) of the mixture versus resveratrol on mitochondrial mass, oxygen consumption and gene expression were measured in human skeletal muscle cells. Finally, synergistic effects (p<0.01) of the phenolic mixture in preventing oxidative damage to DNA (COMET assay) were observed in human pancreatic cells. These results suggest that, compared to isolated plant phenolics, the complex mixtures occurring naturally in plants have greater potency to influence various mechanisms of cellular aging.
Coronary Arteries Injury in a Model of Pulmonary Fat Embolism Syndrome (PES)
Authors: Patel Chirag , Alqalyoobi Shehabaldin , Naji Darwish , Herndon Betty , Poisner Alan , Molteni Agostino
Published: June 2021

Lung inflammation, vasculitis, and fibrosis occur in FES following bone fractures, surgical procedures, and liposuction. We reported the onset of myocardial damage in a rat model of FES with pulmonary fibrosis. This study continues our earlier work with attention to the evolution of the inflammatory process of the coronaries.

Of 28 male SD rats, 14 received 0.2 mL IV triolein (FES model) and 14 received IV saline. Six weeks later, Losartan (0.3 mg/kg) was given IP to half of each group up to ten weeks. At necropsy, the tissues were stained for H&E, SMA‐1, and Trichrome for collagen. Six photos at 400x were made of each heart. The coronary vasculitis was assessed by measurement of the medial thickening and lumen patency.

In addition to the lung fibrosis, the heart of the triolein treated rats showed intense SMA‐1 staining of the coronary media, intima, and adventitia. Lumen patency was reduced versus saline controls (p < 0.05). Losartan and saline treated rats did not differ from controls. Losartan protected the triolein treated rats from the heart damage with mild medial staining and wider lumen patency (p = 0.05). A small rim of collagen (trichrome) was seen in the adventitia of all the rats with more intensity in the triolein treated groups. Losartan reduced its presence.

SMA‐1 staining by evidencing the transformation of fibroblasts and myofibroblasts shows the beginnings of collagen‐induced fibrosis. Would a longer treatment result in a more severe coronaropathy? The protective effect of Losartan was again confirmed underlining the role of the Renin‐Angiotensin system in this disease. Information from this model may help treating patients with FES.
Development of a pretreatment strategy to enhance the efficiency of hepatocyte transplantation in mice
Authors: Hsu Yu Chen , Fan Meng‐Ni , Huang Yu Jen , Yu I‐Shing , Chen Chun‐Yu , Wu Yao‐Ming , Lin Shu‐Wha
Published: June 2021

Hepatocyte transplantation (HTx) is a promising approach for the treatment of genetic liver diseases. However, the poor engrafted efficiency of 0.03‐0.5% of transplanted cells in the recipient livers usually limits the clinical applications. In previous study, we observed an enhanced engraftment of intrasplenically injected cancer cells into the liver of a specific mouse strain due to its narrowed sinusoid, and therefore suspected that narrow sinusoids may enhance the efficiency of HTx. To validate this hypothesis, we transplanted primary hepatocytes by intrasplenic injection into WT C57BL/6 and mice treated with an antibody (Ab) that is known to cause narrow sinusoids of the liver. We found the amount of injected donor cells was nearly 2 times more in the Ab‐treated mice than those in the WT livers at all the time points followed. To confirm the possibility of clinical application of this Ab‐treatment strategy, we tested its therapeutic effect using the hemophilia B disease model. We compared the therapeutic effect between untreated and Ab‐pretreatment strategy on hemophilia B receiving functional hepatocytes for control of bleeding. Transplanted mice were followed for one month, and their sera were analyzed periodically for the activity and antigen levels of coagulant factor IX. We found that mice receiving Ab‐pretreatment strategy had higher FIX antigen and clotting activity than those of untreated groups. Our results showed the Ab that is effective in narrowing the hepatic sinusoids may be useful for improving cell/stem cell therapy for liver diseases in the near future.
Effects of Quercetin and α‐Lipoic Acid on α‐Cypermethrin‐Induced Oxidative Stress in Rats
Authors: Rotimi Solomon , Ugwu Emmanuel , Essien Imaobong , Adelani Isaacson , Rotimi Oluwakemi
Published: June 2021

This study evaluated the effects of quercetin and α‐lipoic acid on the antioxidant status of α‐Cypermethrin (α‐CYP) treated rats. 30 rats were randomly divided five experimental groups thus: (i) control group, (ii) α‐CYP alone (14.5 mg kg‐1 body weight/day, p.o.), (iii) α‐CYP (14.5 mg kg‐1body weight/day, p.o.) and α‐lipoic acid (20 mg kg‐1body weight/day, p.o.) 1h later, (iv) α‐CYP (14.5 mg kg‐1body weight/day, p.o.) and quercetin (20 mg kg‐1body weight/day, p.o.) 1h later (v) α‐lipoic acid alone (vi) quercetin alone. After two weeks of treatment, the rats were sacrificed and blood collected by cardiac puncture and organs were excised for the assay of the activities of antioxidant enzymes and levels reduced glutathione (GSH) and lipid peroxidation. α‐CYP induced a significant (p<0.05) decrease in the activity of superoxide dismutase (SOD) in liver and kidney; and that of glutathione‐S‐tranferase (GST) in liver and erythrocytes. There was also a significant (p<0.05) decrease in the level of GSH in liver, brain and kidney. α‐lipoic acid administration with α‐CYP induced a significant (p<0.05) increase in activity of SOD in liver and levels of GSH in liver, kidney and brain. α‐lipoic acid also induced a significant (p<0.05) decrease in GST activity and lipid peroxidation level in liver and RBC. Quercetin administration had similar effect as alpha‐lipoic acid, only that there was no significant (p>0.05) difference in SOD activity in liver. The results demonstrated that administration of α‐lipoic acid or quercetin to α‐CYP treated rats exerted protective role against oxidative stress and lipid peroxidation.
The Landscape of Drug Discovery in Alzheimer's Disease: an Update on Research and Patenting Activity
Authors: Sohn Eunsoo , Sohn Eun‐Hwa
Published: June 2021

It is generally recognized that Alzheimer's disease (AD) is devastating for the individual, the family and the country from clinical, social and financial vantage points. AD is characterized by the accumulation and deposition of beta‐amyloid within the brain, leading to irreversible neurological damage. Even though the causes of AD still remain unknown, the demand for the treatment is increasing. Since then many researches have been conducted on this issue and its treatment. Herein, we review current research and development status of drug discovery in AD, and discuss the trend of patenting activities.
Analysis of Glial Activation around Brain Metastases of Breast Tumors in a Mouse Model
Authors: Amico‐Ruvio Stacy , Shapovalov Yuriy , Lamantia Cassandra , Spielman Sara , Brown Edward , Majewska Ania
Published: June 2021

Tumor progression is contingent on a well‐orchestrated interplay between tumor cells and the host tissue. Host inflammatory processes in particular can play a prominent role both in systemic breast cancer and in brain tumors. While much literature has explored the contribution of inflammation to the progression of primary cancers, relatively little effort has been made to understand how brain immune cells interact with brain metastases of breast cancer. We have quantitatively characterized the expression of microglial and astrocytic markers around brain metastases of a brain‐homing human breast cancer cell line injected intracardially into nude mice. Using immunohistochemical analyses in fixed brain sections, we show that the inflammatory profile of brain tissue surrounding metastases is complex. We found profound glial activation at the interface with tumor cells as well as altered glial profiles as far as hundreds of microns from the edge of the metastatic tumor. Our results are the first quantitative analysis of glial activation in a mouse model of breast cancer metastasis to the brain and can serve as a foundation for future studies investigating the effects of brain inflammation on metastatic disease.
Effect of Repeated Exposure to Sleep Restriction on Interleukin 6 Levels in Humans
Authors: Bhatt Vrushank , Diolombi Moussa , Haack Monika , Mullington Janet
Published: June 2021

Repeated exposures to sleep restriction with short in‐between periods of recovery sleep are increasingly common in society, in particular for individuals with irregular work schedules. Short periods of experimental sleep restriction have been shown to elevate inflammatory markers, such as interleukin 6 (IL‐6) which has been suggested to increase the risk for cardiometabolic diseases. However, the effect of repeated exposure to sleep restriction on IL‐6 is unknown. Forty‐three healthy participants (age 32+2 yrs; BMI 24+1 kg/m2; 21 men and 22 women) were randomized to a 22‐day study of repeated cycles of sleep restriction (4hr sleep/night for 3 nights followed by one recovery sleep, 4 cycles) or routine sleep (8hr sleep/night). Blood was sampled from fasting recumbent participants in the morning after awakening, during baseline, third day of each sleep restriction or control cycle, and following recovery sleep. Plasma concentrations of IL‐6 were measured using high sensitivity immunosorbent assay (R&D Systems ELISA). The sleep restriction group showed a significant increase in IL‐6 levels during the first sleep restriction cycle, exceeding control levels by 30% (p<0.05). These levels did not return to baseline in the remaining sleep restriction cycles when compared with the control group. IL‐6 levels return to baseline levels after recovery sleep. In conclusion, these findings suggest that repeated patterns of sleep restriction elevate circulating levels of IL‐6 which may contribute to the development of risk for cardiovascular and cardiometabolic diseases. Supported by NIH (HL‐106782).
Regulator of G Protein Signaling 6 (RGS6), a Novel Suppressor of Bladder Carcinogenesis
Authors: Yang Jianqi , Platt Lance , Maity Biswanath , Ibeawuchi Stella‐Rita , Stewart Adele , Huang Jie , Anderegg Simon , Fisher Rory
Published: June 2021

Urinary bladder cancer, the fifth most common cancer in the United States, is largely caused by exposure to toxic chemicals including those from smoking. Polymorphisms in the RGS6 gene leading to increased RGS6 translation are associated with a pronounced reduction in the risk of bladder cancer, especially among smokers. We employed a RGS6‐/‐ mouse line to interrogate the role of RGS6 in BBN‐induced bladder carcinogenesis, a model that closely resembles human invasive bladder cancer. RGS6 is highly expressed in mouse bladders, including urothelium where transitional cell carcinoma originates. Ablation of RGS6 greatly shortened the time needed for BBN‐induced bladder tumor formation (12 wks vs 20 wks in wild type (WT) mice). Consistently, WT mice treated with BBN showed a marked down‐regulation of RGS6 and Gβ5 as well as a transient activation of p53 (phosphorylation of S15), the latter of which was greatly blunted in RGS6‐/‐ mice. Loss of RGS6, either in BBN‐treated WT mice or RGS6‐/‐ mice, also resulted in an increase in DNMT1 in bladder urothelium, consistent with our recent evidence that RGS6 functions as a scaffold to promote DNMT1 degradation. Consequently, expression of tumor suppressor RASSF1A, a direct downstream target of DNMT1, was greatly repressed in RGS6‐/‐ urothelium. Our findings show that RGS6 is a previously unrecognized, but critical repressor of bladder carcinogenesis. Loss of RGS6, observed during BBN‐induced mouse bladder carcinogenesis and in human bladder tumors, would be expected to drive carcinogenesis through impaired p53 activation and increased expression of DNMT1. (Supported by AHA 11SDG7580008 (JY) and NIH CA161882 (RAF))
The molecular requirements for the G protein betagamma‐SNARE interaction
Authors: Zurawski Zack , Wells Christopher , Yim Yun , Alford Simon , Hamm Heidi
Published: June 2021

Inhibitory G‐protein coupled receptors (GPCRs) can attenuate the secretion of hormones and neurotransmitters in an Ca2+‐dependent fashion. It has been shown that one mechanism for this inhibition involves the direct interaction of G‐protein βγ dimers (Gβγ) with the soluble N‐ethylmaleimide sensitive attachment protein receptor (SNARE) proteins syntaxin1A (Stx1A) and SNAP‐25. We have previously shown that Gβγ competes with the calcium sensor synaptotagmin 1 (Syt1) for binding sites upon SNARE proteins in a Ca2+ dependent manner. The goal of this study is to determine the individual residues required for the Gβγ‐SNARE interaction. To investigate the molecular basis for this interaction, prior studies performed by our group utilizing a “peptide mapping” approach have shown that both the N‐terminal and the C‐terminal domains of SNAP‐25 are essential for the interaction of Gβγ with SNAP‐25. Here, utilizing a similar approach, we demonstrate that the N‐terminal Habc domain is essential for the interaction of Gβγ with Stx1A. The interaction is mediated through two positively‐charged residues: K55 and R125. Mutation of these residues to Ala abolishes Gβγ binding in vitro, while retaining the ability to bind Syt1. We anticipate that these studies will enhance our understanding of the GPCR‐mediated regulatory mechanisms of exocytosis.