bluuebunny/crossref_metadata_2025 huggingface dataset:
“Nutrition, Behavior, and Mental Health”: a Unique Undergraduate Course at the Intersection of Food and Mood
Authors: Chen Lenis , Murray‐Kolb Laura E.
Published: June 2021

A new class, “Nutrition, Behavior, and Mental Health,” was taught in Spring 2012 at Johns Hopkins University. The course served as a journey through topics as diverse as micronutrients, caffeine, and eating behaviors to seek nutrition's connection to behavior and mental health. It started with micro‐level nutrient impacts on the brain and eventually moved to macro‐level topics such as eating disorders. In terms of assessment, students were expected to do class readings (including chapter readings from a Nutrition and Behavior text by Worobey et al.) and submit one question per reading assignment, the answer to which was often provided by class lecture. Students were also required to find a weekly scholarly article or news article related to what was being covered in class; they were then asked to write a thought paper containing their reactions to the article. Periodic quizzes were used to check understanding, and a final presentation on each student's topic of choice served as another form of evaluation. Finally, students engaged in a Recipe & Culture activity, in which they were asked to interview a friend or family member about a recipe and its associated cultural traditions. Given the important role that nutrition and mental health play in a public health context, this course aimed to promote awareness of nutrition's role as a modifiable factor in individual behavior and mental health.
Comparison of dynamic model predicted and actual weight gain during overfeeding: An energy balance analysis
Authors: Begum Yasmin , Cupidon Shanakey , Aftab Tasnia , Anazodo Michael
Published: June 2021

Purpose

Dynamic models that predict weight gain from standardized overfeeding protocols overestimate weight gain. The measured components of energy balance from overfeeding experiments in which adherence to energy intake was objectively established offer direction for model revisions.

Methods

Data was obtained from two different overfeeding studies. The Bouchard study, which was supervised in a confined environment, overfed 12 pairs of male twins by an average of 857 kcal/d for 100 days. The adherence in the 8‐week Levine overfeeding study (1000 kcal/d over baseline) was determined using the sum of changed body energy stores and energy expenditures.

Two validated and widely applied weight change prediction models (the Thomas model and the Hall model) were tested against individual weight gain data and model terms (resting energy expenditure and total energy expenditure) from the Bouchard and Levine studies. A Bland Altman analysis comparing actual versus predicted final weight was performed.

Results

There was good correlation between model predicted and actual final weight from the Bouchard study (Thomas: R2=0.93, Hall: R2=0.89). However, the Bland Altman analysis resulted in negative bias; Hall model: bias=−2.9 kg, 95% confidence intervals −8.3, 2.1; Thomas model: bias=−1.7 kg, 95% confidence intervals −6.6, 3.0. Term by term comparison of energy expenditure in the Levine study revealed resting metabolic rate is overestimated during weight gain.

Conclusion

Changes in the components of energy expenditure during weight gain need to be re‐examined to correct for over‐estimation in weight gain.
Associations Between Socioeconomic Status and Dietary Patterns in the REGARDS Study Population
Authors: Kell Kenneth Patton , Judd Suzanne E , Shikany James M , Fernandez Jose R
Published: June 2021

Socioeconomic status (SES), typically assessed by education and income, has been associated with measures of diet quality; however, such measures have not directly captured individuals’ overall eating practices. Based on factor analysis of 56 food groups from food frequency questionnaires, patterns of food consumption were examined for their associations with SES in a nationally representative sample of 21,636 black and white participants (age >; 45) from the REGARDS study. Logistic regression adjusted for age, race, geographic region and sex was used to examine adherence to three emergent dietary patterns (Sweets, Southern, and Plant‐based) according to education (college graduate or high school non‐graduate) and income (>;$75K or <$20K). Based on odds‐ratios (OR) at a p<0.05, college graduates were less likely to adhere to Sweets or Southern dietary patterns than those who did not complete high school (OR=0.76, OR=0.38). Subjects making >;$75k were less likely to adhere to Sweets or Southern patterns than those making <$20k (OR=0.62, OR=0.43). When evaluating Plant‐based patterns, greater adherence was observed in college graduates (OR=1.84), with white college graduates having greater adherence than black (OR=2.18, OR=1.41). Further research is needed to understand the interactions of SES, food intake and health risk in the diverse US population.

Grant Funding Source: UAB NORC Grant: P30DK056336 and NHLBI Grant: T32HL105349
Metabolic status of adipocytes triggers rapid adjustments of systemic glucose tolerance
Authors: Kless Caroline , Klingenspor Martin
Published: June 2021

Adipose tissue expansion is one potential cause for impaired systemic glucose tolerance (GT). In three inbred mouse strains with different susceptibility to diet‐induced obesity (DIO) we monitored GT after high fat feeding and in response to caloric restriction.

Male AKR/J, SWR/J and C57BL/6J mice received high‐fat diet (HFD, 48 kJ% fat) or control diet (CD, 12 kJ% fat) for 12 weeks, followed by either refeeding of CD or restricted pair‐feeding with HFD. Body mass, body composition, energy intake, energy expenditure and oral GT were measured regularly.

Acutely, HFD feeding for 1.5 days increased energy intake and reduced GT in all three strains. During prolonged HFD feeding, DIO prone AKR/J and B/6J mice, but not DIO resistant SWR/J mice, maintained impaired GT. Refeeding CD or pair‐ feeding HFD of obese AKR/J mice normalized normalized GT rapidly.

These results demonstrate that HFD triggers a fast reduction of GT, independent of DIO susceptibility. This is an acute metabolic response to the increased utilization of fatty acids as energy substrates. Impaired GT is only maintained in mouse strains prone to DIO suggesting an important contribution of anabolic metabolism of adipocytes whereas shifting towards a catabolic state of adipocytes rapidly normalizes GT.

This work was supported by BMBF FKZ 0315674 to MK.
Bone mechanical competence in hypercholesterolemic rats fed MUFAn9 rich diets.
Authors: Alsina Estefania , Bozzini Clarisa , Macri Elisa , Lifshitz Fima , Rodriguez Patricia , Boyer Patricia , Friedman Silvia
Published: June 2021

Reduced bone mass in growing rats fed MUFAn9‐rich diets was observed. But bone stiffness has not been defined yet. To study the mechanical bone competence in hypercholesterolemic (HC) rats fed MUFA diets, weanling male Wistar rats (n=48) were assigned to one of 7 diet groups for 8 weeks (T8). Three control groups fed a commercial diet (C), C+olive oil (COO) or C+high‐oleic sunflower oil (CHOSO) and 4 groups, an atherogenic diet for 3 weeks; then either one of OO, HOSO, HOSO+sterols or HOSO+fish oil diet. At T8, serum lipid‐lipoprotein profile and femur mechanical properties were assessed: Load‐bearing capacity, yielding load and deformation, stiffness, Cross‐sectional bone area, Cortical Area, moment of inertia, yield stress, elastic modulus. Body weight was lower in HOSO (p<0.0001). HOSO had the highest T‐chol & nHDL & the lowest HDL. HOSO+fish oil, the lowest T‐chol & nHDL. HOSO+sterols oil improved HDL, nHDL & T‐chol vs. HOSO (p<0.01). Structural & geometric properties were negatively affected but material bone quality properties remained unchanged in HC. The impaired mechanical bone competence in HC could be due to an altered bone mass and architectural distribution rather than to intrinsic bone quality with detrimental effects on femoral stiffness and strength. UBACyT 0613 and 0070 and Ped Sunshine Acad USA grants. Champin G technical support.
Parenteral lipid minimization versus composition for intestinal failure associated liver disease
Authors: Josephson Jessica K , Wales Paul W , Nation Patrick N , Wizzard Pamela , Mager Diana , Field Catherine J , Ball Ronald O , Pencharz Paul B , Turner Justine M
Published: June 2021

Introduction

Strategies to treat intestinal failure associated liver disease (IFALD) manipulate dose or composition of parenteral lipids. We compared low dose omega‐6 (soybean oil), low dose omega‐3 (fish oil) and standard dose therapies using soybean or a combination of soybean, medium chain triglycerides, olive and fish oil, on liver and nutritional outcomes in neonates.

Materials and Methods

Neonatal pigletswere allocated to: Group 1 (n=6) Omegaven® at 5 g/kg/d, Group 2 (n=8) Intralipid® at 5 g/kg/d, Group 3 (n=9) Intralipid® at 10 g/kg/d, Group 4 piglets (n=10) SMOFlipid ® at 10g/kg/d and Group 5 sow‐reared controls (n=8). After 14 days of total parenteral nutrition we compared bilirubin, bile flow, weight and brain weight.

Results by Group (mean/SD)

1
2
3
4
5

Total Bilirubin (microM/L)
7.0a (5.3)
10.8a (3.2)
21.1b (10.7)
4.0c (1.2)
8.2a (3.9)

Bile flow (mcg/g liver)
12.3a (6.8)
7.9a (3.8)
5.4b (4.0)
13.5a (6.6)
9.0a (1.9)

Total weight gain (kg)
2.7a (0.2)
2.4a (0.3)
2.2a (0.5)
3.0c (0.3)
3.9b (0.9)

Brain weight (g)
35.3a (1.8)
36.3a (3.3)
41.6ab (4.6)
44.2b (3.4)
45.9b (3.4)

Superscripts refer to differences by ANOVA p<0.05

Discussion

Groups 1, 2 and 4 were equally effective in preventing IFALD. Based on weight gain and final brain weight SMOFlipid ® provides beneficial nutritional support to vulnerable neonates, while protecting from cholestasis.

The source of research support is CIHR with Fresenius Kabi

Grant Funding Source:CIHR
Genetic C677T polymorphisms of methylenetetrahydrofolate reductase and one‐carbon metabolites as prognostic predictors for survival outcome of patients with hepatocellular carcinoma.
Authors: Kuo Chang Sheng , Hwung Chyi‐Yun , Kuo Shine‐Dou , Cheng Chin‐Pao , Chen Chien‐Hung , Lu Chin‐Li , Huang Rwei‐Fen
Published: June 2021

The aims of this study were to investigate the association between methylene‐ tetrahydrofolate reductase(MTHFR) C677T polymorphism, two thymidylate synthase(TS) polymorphylisms (a tandem‐repeat of 5′UTR and 6‐bp ins/del polymophylism on the 3′UTR), one carbon‐status and survival rates of patients with hepatocellular carcinoma (HCC). The cohort study included 232 HCC patients. MTHFR C677T and TS polymorphisms were analyzed by real‐time PCR. Survival outcome of HCC patients was analyzed by Kaplan–Meier method and Cox proportional hazard model. The results showed that Cox elevated serum AFP (>;200 vs. <20, HR=3.61, CI=1.99–6.55), vitB12(>;1500 vs. <699, HR=2.69, CI =1.24–5.84), RBC folate (>;818 vs. <566, HR=2.05, CI=1.11–3.78), overweight (>;24 vs. <18.5, HR=4.86, CI=1.11–21.17) and increase tumor size (5~10 vs. <5, HR=1.97; CI=1.18–3.27) will elevate the hazard ratio of HCC death. MTHFR 677 CT or TT genotypes were associated with reduced hazard ratio of HCC death (CT/TT vs. CC, HR=0.48; CI=0.30–0.79). CC genotype in combination with high folate status (566–818 ng/mL) or with elevated vitamin B12 levels (699–1500 ng/ mL) were associated with increased HR (HR=2.02, 95%CI=1.00–4.11) for RBC; (HR=2.04, 95% CI=1.11–3.77) for vitamin B12. Taken together, folate, B12 and MTHFR C677T polymorphism serve as the potential predictors for survival outcome of HCC patients.
In vitro inhibition of dipeptidyl peptidase IV by amaranth peptides
Authors: Velarde‐Salcedo Aida J. , Lara‐González Samuel , Monero‐Morán Gabriela M. , de Mejia Elvira Gonzalez , Barba de la Rosa Ana P.
Published: June 2021

Dipeptidyl peptidase IV (DPPIV) is an enzyme that acts deactivating incretins, the hormones involved in insulin secretion and is being considered as target against diabetes. The objective was to investigate the inhibitory activity against DPPIV of amaranth peptides released after tryptic digestion and after in vitro simulated gastrointestinal digestion. Amaranth glutelins fraction showed the highest inhibitory activity against DPPIV in a dose‐dependent manner with an IC50 =1.6 mg/mL. Proteins from other seeds such as wheat, common beans and soybean were tested. The ligand‐enzyme docking simulations using peptides from amaranth globulins released by tryptic digestion showed that peptides larger than 13 amino acids are able to interact with DPPIV enzyme at the dimerization domain. Shorter peptides were located inside the large cavity of DPPIV where natural substrates are digested. The predicted interaction energy of the peptides ranged from −5.98 to 9.48 kcal/mol. In conclusion, our results indicate that amaranth peptides released after digestion are able to inhibit DPPIV by binding the active and dimerization domains. This function has the potential for amaranth peptides to act as antidiabetic compounds.

Grant Funding Source: Ministry of Health, Mexico, Fondo Sectorial Salud No. 150873
Infant intake patterns vary by feeding method: results from a randomized controlled trial
Authors: Maalouf‐Manasseh Zeina , Chantry Caroline , Dewey Kathryn G
Published: June 2021

Formula feeding is associated with greater intake and more rapid weight gain than breastfeeding. It is unclear if this is due to differences in composition of formula vs. human milk or the practice of feeding by bottle. We conducted a randomized controlled trial in which 231 infants whose mothers planned to provide at least some of the feeds (formula or human milk) by bottle were assigned to a novel bottle with a nipple allowing the infant more control over the flow of milk, or a conventional bottle. We also compared intake of human milk when consumed by bottle vs. at the breast. In infants who were fed only formula, intake per feed was lower with the novel vs. conventional bottle at both 3 mo (112 vs. 135 g, p=0.076) and 4 mo (129 vs. 152 g, p=0.039). However, the number of feeds/d was higher in the novel bottle group (15.2 vs 13.5, p=0.12 at 3 mo; 16.0 vs. 13.4, p=0.055 at 4 mo) and thus there was no significant difference between groups in 24‐h intake. In infants fed only human milk, intake per feed was greater when fed directly at the breast (87 g) than when fed by bottle (75 g, p=0.048) at 3 mo, but there were no differences in intake/feed or 24‐h intake between intervention groups at 3 or 4 mo. These results suggest that a novel bottle nipple that allows greater infant control over the rate of intake results in lower intake per feed, but that infants compensate over 24 hours by increasing feeding frequency.

Research support provided by the National Institute of Child Health & Human Development, Grant Number: 1RC1DK087234.
Caffeine intake and the plasma proteome
Authors: Tian Ouxi , Josse Andrea R , El‐Sohemy Ahmed
Published: June 2021

Caffeine intake has been associated with both an increased and decreased risk of various health conditions. However, the physiological pathways affected remain unclear. CYP1A2 is the major enzyme that metabolizes caffeine and a single nucleotide polymorphism (rs762551) affects the rate of caffeine metabolism. The objective of this study was to determine whether caffeine intake is associated with proteins in the plasma proteome, and whether CYP1A2 genotype modifies any of the associations observed. Subjects (n=1095) aged 20–29 years completed a 196‐ item semi‐quantitative food frequency questionnaire and provided a fasting blood sample from which DNA and plasma were obtained for genotyping and proteomic analysis with 54 plasma proteins. Subjects were categorized into three groups according to habitual caffeine intake (<100mg/d, 100–200mg/d, and >;200mg/d) and later stratified by CYP1A2 genotype. Among individuals with A/C or C/C genotypes (slow metabolizers), plasma concentration of complement component 3 (p=0.03) and gelsolin isoform 1 (p=0.005), were significantly lower in the highest category of caffeine intake. No differences in protein concentration were observed for A/A individuals (fast metabolizers). These results suggest certain plasma proteins are affected by caffeine intake, but only among slow metabolizers.

Grant Funding Source: Canadian Institutes of Health Research
Hyperglycemia mediates a shift from cap‐dependent to capindependent mRNA translation through a 4E‐BP1 dependent mechanism
Authors: Dennis Michael D , Kimball Scot R , Jefferson Leonard S
Published: June 2021

In both liver of diabetic mice and cells in culture exposed to hyperglycemic conditions 4E‐BP1 is modified by OGlcNAcylation concomitant with enhanced expression and interaction with the mRNA cap‐binding protein eIF4E. Interaction of 4E‐BP1 with eIF4E plays a major role in the regulation of gene expression by controlling the selection of mRNAs for translation. In the present study, we evaluated the hypothesis that hyperglycemia alters the profile of mRNAs selected for translation. Using pulsed stable isotope labeling by amino acids in cell culture (pSILAC) we identified proteins with altered rates of synthesis upon exposure to medium containing 25 compared to 5 mM glucose. The mRNAs encoding proteins whose synthesis was most enhanced contained longer, more complex 5′‐UTRs, suggesting hyperglycemia favors the translation of mRNAs with more structured 5′‐UTRs, including those containing internal ribosome entry sites. Using a bicistronic luciferase reporter assay, the high glucose condition also caused a repression of cap‐dependent and enhancement of cap‐independent mRNA translation. Notably, the glucose‐induced shift from cap‐dependent to cap‐independent mRNA translation did not occur in cells lacking 4E‐BP1. (Supported by NIH grant 13499 (LSJ) and an NIH Postdoctoral Fellowship (MDD))

Grant Funding Source: NIH 13499
Proteomic profiling of thyroid follicular adenoma
Authors: Lai Xianyin
Published: June 2021

Thyroid follicular adenoma (FA) is a benign tumor of the thyroid gland where cells produce iodine‐containing hormones. FA can precede either follicular carcinoma or papillary carcinoma. To discover the molecular mechanism involved in follicular adenoma, diseased and matched normal adjacent tissue were analyzed by liquid chromatography tandem mass spectrometry (LC‐MS/MS). Using a label‐free quantitative mass spectrometry‐based proteomics approach, IdentiQuantXL, 1,799 unique, non‐redundant proteins were compared between FA and normal tissue samples. Among the 1,799 proteins, 15 proteins had significant changes (p ¡Ü 0.05) between the two groups. Using Ingenuity Pathways Analysis (IPA), their molecular and cellular functions were discovered, including cell‐to‐cell signaling and interaction, cell cycle, cell death and survival, cell morphology, and cellular assembly and organization. Among the 15 proteins, 6 proteins were cancer‐related. In conclusion, differential protein expression was observed, which may reveal the mechanism in the development of follicular adenoma.
Role of C‐terminal domain of E‐cadherin in activating β‐catenin/TCF pathway in cancer cells under hypoxic conditions
Authors: Sellak Hassan , Wu Songwei , Lincoln Thomas M.
Published: June 2021

E‐cadherin expression plays a predominant role in the development and homeostasis of epithelial architecture. Down‐regulation of transmembrane protein E‐cadherin is often considered as a marker for cancer malignancy and metastasis. In this study, the effect of hypoxia on E‐cadherin expression in different cancer cell lines was analyzed. We hypothesized that down‐regulation of E‐cadherin under hypoxia would lead to transmigration of its intracellular C‐terminal fragment to the nucleus and result in activation of ß‐catenin/ TCF pathway. Treatment of A549 lung cancer, SW480 and SW620 colon cancer, T47D breast cancer, and HEK293 cells with hypoxia, 1% oxygen for periods of two, three, or four days, resulted in a significant decrease in E‐cadherin expression, Under hypoxic conditions, E‐cadherin is highly degraded resulting in the generation of multiple bands of different molecular weights depending on cells and involved proteinases. This decrease in E‐cadherin is concomitant to an increase in Snail and Slug expression, well‐known E‐cadherin suppressors. Similarly, over‐expression of Snail and Slug in cancer cells resulted in an increase in TCF activity quantified by a luciferase assays. Finally, transient transfection of cancer cells with cloned soluble C‐terminal E‐cadherin resulted in high TCF activity compared to the control. These results suggest that in normoxia, E‐cadherin neutralizes ß‐catenin and prevent it from inducing nuclear TCF activity. However, following E‐cadherin degradation, C‐terminal E‐cadherin binds ß‐catenin and translocates to the nucleus to activate TCF.
Rapamycin‐Regulated Ubiquitin Specific Peptidases Expression in Cardiocytes
Authors: Zanetti Arthus Vilar Deolindo , Santos Lucas Carvalho , Schoeps Vinicius Andreoli , Sanzovo Paula Sajovic , Carniello Jose Victor Scarpa , Manso Andre Augusto Simoes , Sellke Frank William , Bianchi Cesario
Published: June 2021

INTRODUCTION

The mechanistic target of rapamycin (mTOR) regulates protein degradation through autophagic/lysosomal activity. However, the mTOR effects on protein degradation by the ubiquitin/proteasome pathway have not been established. Protein ubiquitination is regulated by a balance of polyubiquitin ligases and ubiquitin specific peptidases (USP).

OBJECTIVE

To determine whether mTOR inhibition could modify the ubiquitin/proteasome pathway.

METHODS

Pigs were treated with placebo or 4mg/daily rapamycin (RAPA; mTOR inhibitor) for 1 week (n=5/group). H9C2 (cardiomyocytes) cells were cultured in DMEM and treated with 600 nM RAPA for up to 3 days. RNA and protein levels were quantified by q_PCR and western blotting and statistically analyzed (ANOVA / t‐Test).

RESULTS

RAPA treatments inhibited mTOR [lower p‐P70S6K(T389)] both in vivo and in vitro. In vivo RAPA decreased protein levels of USP11 and 28 and in vitro RAPA decreased mRNA levels of USP11, 24, 28 and 39 and proteins levels of USP28 and 39 that were associated with increased total protein ubiquitination.

CONCLUSION

These results document the regulation of the ubiquitin/proteasome pathway by mTOR and reveals that mTOR activity may regulate cellular protein levels through degradation by both lysosomal and proteasomal pathways. Further studies will address the importance of RAPA‐regulated USP11, USP28, and USP39 levels in cardiac cells.
α1‐Adrenergic receptor (α1‐AR) activation rapidly upregulates L‐type Ca2+ channels in rat mesenteric arteries in vivo
Authors: Srivastava Anup Kumar , Kharade Sujay V. , Fletcher Terry W. , Rhee Sung W. , Rusch Nancy J.
Published: June 2021

Activation of the α1‐adrenergic receptor (α1‐AR) in small mesenteric arteries (MA) is a critical pressor mechanism presumed to rely on Ca2+ mobilization for vasoconstriction. We hypothesized that α1‐AR agonists also rapidly upregulate vascular L‐type Ca2+ (Cav1.2) channels to dynamically increase vascular tone. MA were exteriorized in intestinal loops of anesthetized Sprague‐Dawley rats to evaluate expression of the Cav1.2 channel α1C pore‐forming protein in response to local application of the α1‐AR agonist, phenylephrine (PE, 1–3 μmol/L). MA were removed initially (0 hr) and again after 3 hr exposure to control or PE‐containing physiological saline solution (PSS); blood pressures were stable during the study. Western blots showed similar expression of the α1C pore protein at 0 hr and 3 hr in control MA, whereas α1C expression increased 1.6‐fold in MA exposed to PE for 3 hr (n=3). MA exposed to KCl (30 mmol/L)–containing PSS showed a 2.9‐fold increase in α1C by 3 hr (n=3), implicating membrane depolarization as a strong stimulus of Cav1.2 channel upregulation. Parallel patch‐clamp studies indicated robust Ca2+ currents in MA smooth muscle cells. In summary, we report a new method to track changes in vascular ion channel expression in vivo and provide evidence that α1‐AR signaling rapidly upregulates Cav1.2 channels in small MA as a novel vasopressor mechanism. Funded by NIH R01 HL064806 (NJR).
TCP‐1 as a novel phage‐display peptide targeting colon cancer
Authors: Lan Lu , Hin Cho Chi
Published: June 2021

TCP1 is a novel vasculature‐targeting peptide. It was discovered through the in vivo phage library selection. It was demonstrated that TCP1 peptide exhibited the homing ability to the tumor neovasculature and was capable of efficiently delivering imaging agents and chemotherapeutic drugs to this target site. The current study is to further investigate the targeting ability of TCP1 to deliver anti‐cancer drugs and imaging agents, and demonstrate the specificity of TCP1 on the putative target on tumor blood vessels and explore the potential mechanisms.

In this study, we observed that TCP‐1 peptide delivered GFP only to tumor blood vessel other than normal organs after GFP or TCP‐1/GFP injection. Results in TNF‐α or TCP‐1/TNF‐α targeted delivery showed that TCP‐1/TNF displayed stronger effects than TNF‐α alone in the induction of apoptosis and reduction in number of microvessels in the tumors but without significant effect in systemic toxicity.

To identify the cell surface targets for TCP1, we incubated the colon 26 cell with biotin‐TCP1 probe peptide and performed the pull‐down assay by neutravidin‐agarose beads. Preliminary western‐blot data showed that some membrane proteins on colon 26 cells could bind to TCP1 after incubation with biotin‐TCP1 probe.

Taken together TCP1 peptide appears to be a promising agent in molecular imaging and drug delivery for gastrointestinal cancers.
Bifidobacteria confer protection against NSAID‐enteropathy independently of acetate production
Authors: Syer Stephanie D. , Martin Rebeca , McKnight G. Webb , Langella Philippe , Wallace John L.
Published: June 2021

Rats were orally treated with vehicle or Bifidobacterium longum subsp. Adolescentis (BA), a low acetate producer, or B. longum subsp. longum (BL), a high acetate producer (both at 109 CFU), for 9 days. In addition, two isogenic strains were also tested: a second BL strain (BN) and its derivative (BNKO) in which a gene deletion results in low acetate production. Naproxen (20 mg/kg) was co‐administered on the final 4 days, then small intestinal damage was blindly scored.

Treatment with BA decreased naproxen‐induced intestinal damage by 82%; p<0.05, while BL exerted no effect. BN reduced damage by 75% (p<0.05), and a similar beneficial effect was observed with the low acetate‐producing knockout bacterium, BNKO (62% reduction; p<0.05).

Small intestinal injury by NSAIDs is a serious clinical problem, with no available treatments. Acetate production by these Bifidobacterium strains does not appear to be important for prevention of NSAID‐enteropathy, given that a high acetate producing Bifidobacteria (BL) exhibited no protective effect, while a low acetate‐producing mutant (BNKO) was as effective in reducing damage as another high acetate‐producing bacterium (BN).
GPR124 coupling and function in astrocytomas
Authors: Cherry Allison , Lin Yi Hsing , Hague Chris , Ong Shao‐En , Stella Nephi
Published: June 2021

GPR124 is an orphan receptor that belongs to the Adhesion GPCR family. Members of this family are characterized by long N‐terminal segments that contain many of the same functional domains found in cadherins, integrins, and tyrosine kinases, but are typically absent in GPCRs belonging to other families. While little is known about adhesion GPCRs, recent results show that GPR124 plays a role in endothelial cell migration and differentiation during angiogenesis. We found that GPR124 mRNA is highly expressed by various human astrocytoma cell lines. Due to the high expression of GPR124 in GBM cells and its known role in cellular migration and differentiation, we hypothesize that these orphan receptors control the migration of GBM cells through specific signal transduction pathways and thus represent promising new therapeutic targets to treat brain tumors.

To test our hypothesis, we used a proteomics approach to determine the effector proteins that couple to this GPCR and measured the migration of human GBM cell lines expressing various levels of GPR124. Myc‐tagged GPR124 was heterologously expressed in the human GBM cell line U87MG and the proteins associated with these receptors were analyzed by Stable Isotope Labeling of Amino Acids in Cell Culture (SILAC) mass spectrometry. We found a concise list of effector proteins that are known to control cell migration. To determine if GPR124 levels affect cell migration, we used a modified Boyden chamber assay that was developed in our laboratory. We found that GPR124 over‐expression increases the migration of U87MG cells stimulated by lysophosphatidic acid (LPA). Together, our results suggest that GPR124 is expressed by astrocytomas and tightly regulates how these cells migrate toward select chemokines.
Lipopolysaccharide‐Induced Upregulation of Cannabinoid 2 Receptors in Rat Cortical Astrocytes
Authors: Jackson Dakota N , Shivachar Amruthesh
Published: June 2021

While the existence of cannabinoid 2 receptors (CB2R) in healthy brain is still uncertain, its expression is associated with a variety of inflammatory processes. Activation of CB2R in microglial cells is known to suppress the release of pro‐inflammatory factors that cause astrogliosis ‐an inflammatory brain response. The aim of this study was to determine whether inflammatory agents, such as bacterial lipopolysaccharide (LPS), alter the expression of CB2R in astrocytes. In this study, rat cortical astrocytes (RCAs) were treated for 24hr (0–10mcg/mL) in serum free Dulbecco's Modified Eagle Medium (DMEM). The expression of glial fibrillary acidic protien (GFAP), as a measure of “astrogliosis”, and expressions of CB1R and CB2R were measured by immunocytochemistry (IC) double labeling and quantitative western blot (WB) analyses. IC results showed that 24hr incubation with LPS increased the number of fibrous‐like processs in GFAP‐expressing cells that also showed an increase in the expression of CB2R. Quantitative WB analysis confirmed our IC results, showing a 2‐fold increase in CB2R band intensity. WB analysis also showed an increase in CB1R expression in astrocytes. These results indicate that LPS treatment induces astrogliosis with a concomitant upregulation of CB2R expression in RCAs.
A behavioral assessment of the aversive properties of delta‐9‐ THC in Fischer‐Lewis rats.
Authors: Presley Alison , Riley Anthony
Published: June 2021

Although Lewis (LEW) and Fischer (F344) rats differ in their sensitivity to the rewarding effects of THC, no data have been reported on differences in their sensitivity to the drug's aversive effects, a limiting factor in drug use and abuse. Examining the degree of differences (if any) in such effects in these strains may help further characterize the factors important to abuse vulnerability. Accordingly, the aversive effects of THC were examined in 32 F344 and 32 LEW subjects using the conditioned taste aversion procedure. Core body temperatures were also examined 2 weeks following the final conditioning cycle. Subjects in both strains displayed dose‐dependent THC‐induced taste aversions, with no significant strain difference. Core body temperatures of F344 subjects were significantly higher than LEW rats, although these differences were independent of THC (which itself induced hypothermia in both strains). These results suggest that the reported differences between the strains in THC self‐administration reflect differences in the drug's rewarding (and not aversive) effects and that such aversions are not due to druginduced hypothermia.

This research was funded by a grant from the Mellon Foundation.
The Type of Production System Affects the Polyphenolic and Flavonoid Content of the Gourmet Mushroom, Hericium erinaceus
Authors: Sobel Bryan , Guo Huiyan , Mudge Kenneth , Liu Rui Hai
Published: June 2021

The mushroom, Hericium erinaceus, has received attention for its functional properties. Some of those properties may be related to phenolic and flavonoid compounds, which are believed to promote positive health outcomes. The objective of this study was to determine the effect of production system on the phenolic and flavonoid content of the gourmet mushroom, Hericium erinaceus. Mushrooms were grown in an indoor commercial system, on a prepared substrate or in a forest farming system, outdoors, on a wooden log substrate. Concentrations of phenolic compounds were determined using a Folin‐Ciocalteu based assay. Flavonoid concentrations were determined through a sodium borohydride/chloronil based assay. Units are expressed, based on the standard, in gallic acid equivalents (GAE) for phenols, catechin equivalents (CE) for flavonoids, ascorbic acid equivalents for antioxidant capacity. All measurements are adjusted for moisture content and based on 100 g samples. Commercial mushrooms were (34.17 +/− 1.19 mg GAE & 108.95 +/− 6.98 mg CE) significantly less than forest farmed mushrooms that were harvested in the spring (240.61 +/− 12.80 mg GAE & 595.33 +/− 22.03 mg CE) and fall (313.2±16.8 mg GAE & 1162±108 mg CE) of 2011. Data indicates that mushrooms grown in a more ecologically based production system may contain greater concentrations of potentially health promoting compounds.

Grant Funding Source: McIntire‐Stennis
Evaluation of Oral Dabigatran Etexilate Pharmacokinetics and Pharmacodynamics in Hemodialysis Patients
Authors: Goralski Kerry , Morrison Matthew , Mossop Paula , Soroka Steven , Anderson David , Wilson Jo‐Anne
Published: June 2021

Background

Dabigatran etexilate represents a possible improved alternative to warfarin for anticoagulation in hemodialysis patients with atrial fibrillation (AF). The object was to determine dabigatran plasma concentrations and anticoagulant effects following administration of a single 110 mg oral dose of dabigatran etexilate to hemodialysis patients.

Methods

Dabigatran etexilate (110 mg) was administered to 10 adult patients (25–69 yrs‐old) of the CDHA Renal Program immediately prior to starting hemodialysis. Plasma and dialysate samples were collected intermittently over 48 hours. A thrombin‐based hemoclot assay was used to determine sample‐clotting times, which were compared to dabigatran standards to estimate sample dabigatran concentrations.

Results

The mean time (tmax) to reach maximum plasma concentration (Cmax) was 2.1 hours, and the Cmax was 72.8 ± 31.5 ng/mL. The mean elimination half‐life on hemodialysis (t1/2ON) was 1.1 hours and the half‐life off hemodialysis (t1/2OFF) was substantially longer (41.0 hours).

Conclusions

A 110 mg oral dabigatran dose prior to hemodialysis was rapidly absorbed and achieved therapeutic concentrations. Hemodialysis effectively removed dabigatran from the plasma and is a possible mechanism for dabigatran detoxification.

Funding was provided by the Faculty of Health Professions, Dalhousie University and the Division of Nephrology, CDHA
Rock Inhibition Reduces Senescent Cell Size
Authors: Simay yaprak dilber , Hosbas sanem , Ibisoglu burcin , Yildiz metin , Ozdemir aysun , Ark mustafa
Published: June 2021

Recently drug‐induced senescence has gained importance in cancer therapy. It has been demonstrated that cardiac glycosides induce senescence in several cancer cell lines. On the other hand, small G protein Rho is involved in the formation of morphological features of the senescent cells. However, there is no report whether Rho kinases, important effectors of Rho, contribute to the development of the senescent morphology in cancer cell lines. In the current work, we evaluated this possibility in the cardiac glycoside‐induced senescence in HeLa cells. The xCELLigence real time cell analyzer system, senescence associated β‐galactosidase staining and cell size measurements were used to determine ouabain‐induced senescence. Cells were treated with high (0.1–1 μM, 48h) and low concentration (10–30 nM, 48h) of ouabain. In contrast to the treatment of ouabain in high concentrations which resulted in cell death, low nanomolar concentrations of ouabain induced senescence in HeLa cells. Although preincubation of specific Rock inhibitor Y‐27632 (0.1–10 μM, 30 min) did not inhibit the occurrence of ouabain‐induced (30 nM) senescence in cells, it reduced the cell size. Our results indicate that instead of the induction of senescence, rho kinases involves in the development of drug‐induced senescence morphology.

This study was supported by TUBITAK in 110S426 project.
Alcohol exposure increases fibroblast growth factor 21 expression
Authors: Zhao Cuiqing , Liu Yanlong , McClain Craig , Feng Wenke
Published: June 2021

Long‐term excess alcohol exposure leads to alcohol liver disease (ALD). Alcohol‐induced hepatic fat accumulation sensitizes the liver to various “second hits” to develop more advanced liver injury. Recombinant FGF‐21 has beneficial effects in promoting adipose tissue glucose uptake, lowering circulating glucose levels, and reducing hepatic lipid content in diabetic and obese rodent and monkey models. Serum FGF‐21 is elevated in non‐alcoholic fatty liver disease, coronary heart disease and type 2 diabetes. Serum levels of FGF‐21 were significantly higher in alcoholic patients with and without liver disease. Alcohol ingestion caused a significant increase in hepatic FGF‐21 expression and elevation of serum FGF‐21 concentration in mice exposed to chronic, acute or chronic‐binge alcohol. Incubation of hepatocytes with alcohol also increased FGF‐21 mRNA expression in a dose‐dependent manner. Alcohol significantly decreases hepatic and adipose mRNA levels of FGFR4 and β‐klotho, which is a specific co‐receptor for FGF‐21. Alcohol impaired recombinant FGF‐21‐induced ERK‐1/2 phosphorylation in adipose tissue and liver in mice treated with Lieber deCarli diet containing 5% alcohol for 4 weeks. We demonstrated that alcohol exposure increases hepatic expression and serum concentration of FGF‐21, which are associated with hepatic and adipose tissue FGF‐21 resistant in ALD.
The upregulation of skeletal muscle inflammatory genes links inflammation with impaired insulin resistance in women with the metabolic syndrome
Authors: Hopman Maria T.E. , Lammers Gerwen , Poelkens Fleur , Tack Cees J.
Published: June 2021

The metabolic syndrome is a combination of interrelated metabolic risk factors that promote the development of cardiovascular diseases and type 2 diabetes mellitus. A close link with inflammation exists, but the underlying mechanisms remain elusive. Therefore, the aim of this study was to identify differentially expressed inflammatory genes in insulin resistant skeletal muscle tissue of women with the metabolic syndrome compared to healthy controls. Physical characteristics and blood plasma levels of 19 women with the metabolic syndrome and 20 healthy controls were determined. Insulin resistance was determined using a hyperinsulinaemic euglycaemic clamp and a muscle biopsy was obtained. Gene expression levels were determined for six women in each group using microarrays. As expected, there was a significant correlation between insulin resistance and percentage of total fat mass. The upregulated genes in skeletal muscle of these women were primarily enriched for inflammatory response‐associated genes. The three most significantly upregulated of this group, interleukin 6 receptor (IL6R), histone deacetylase 9 (HDAC9), and CD97 molecule (CD97) correlated with insulin resistance in all women. This suggests an important role for these inflammatory‐related genes in the development of skeletal muscle insulin resistance.

Funding: GL by GO‐EFRO, FP by ZonMW
Telemetry‐based oxygen sensor to continuously monitor renal cortical oxygenation in the conscious rat
Authors: Koeners Maarten Paulus , Ow Connie P.C. , Evans Roger G. , Russell David M. , Joles Jaap A. , Malpas Simon
Published: June 2021

Multiple forms of acute and chronic kidney disease are associated with renal tissue hypoxia. Yet the precise roles of hypoxia in the initiation and progression of kidney disease remain unresolved. A major technical limitation has been the absence of methods allowing long‐term measurement of kidney tissue oxygen concentration in unrestrained animals. Previously we developed a fully implantable telemetric method for the measurement of tissue oxygen concentration in the renal medulla of freely moving rats, using carbon past electrodes (CPEs). Using this CPE‐telemetry system we continuously recorded tissue oxygen concentration in the renal cortex for 3 weeks in rats. Oxygen values were stable over time and comparable between animals. It also provided reproducible responses to systemic hypoxia and hyperoxia over this time period, and these responses were similar to those previously observed in the renal medulla. There was little evidence of fibrosis or scarring after three weeks of electrode implantation. This new technology provides, for the first time, the opportunity to examine the temporal relationships between tissue hypoxia in different renal compartments and the progression of renal disease. EU, FP7, Marie Curie Actions, International Outgoing Fellowship.
Connecting Tubule Glomerular Feedback (CTGF) in Dahl Salt‐Sensitive (Dahl S) and Spontaneously Hypertensive Rats (SHR)
Authors: D'Ambrosio Martin A. , Wang Hong , Garvin Jeffrey L. , Ren YiLin , Carretero Oscar A.
Published: June 2021

Increasing Na delivery to the distal nephron causes connecting tubule glomerular feedback (CTGF) that dilates the Af‐Art. Augmented CTGF may allow increased transmission of systemic pressure to the glomerulus, leading to sustained elevations in glomerular capillary pressure (PGC). In hypertension, this would result in glomerular damage. Hypertensive Dahl S fed high salt have higher PGC and glomerular damage than SHR with similar blood pressure. We hypothesized that this is due to enhanced CTGF in Dahl S compared to SHR. We used in vivo micropuncture of single nephrons. Stop‐flow pressure (PSF) was measured as an index of PGC. CTGF was measured as the difference between two consecutive PSF curves generated by raising nephron perfusion from 0 to 40 nL/min before and during blockade of CTGF with benzamil. Dahl S displayed an enhanced CTGF response compared to Dahl R (P < 0.001), and this was exacerbated by high salt feeding (P < 0.001). The results in Dahl S are in stark contrast with those in SHR. SHR displayed little or no CTGF under normal salt diet. SHR had a reduced CTGF compared to WKY (P < 0.001) and to Dahl S (P < 0.001). In conclusion, under normal salt feeding Dahl S have significant CTGF, while SHR have little or no CTGF. High salt enhances CTGF in all rat strains, especially in Dahl S. Increased CTGF may cause an increase in PGC and enhance hypertensive renal damage.

Supported by NIH Grants HL028982 and HL088036.
Computer modeling of peristaltic contraction and solute concentration in 3D inner medulla of the rat
Authors: Lee Pilhwa , Beard Daniel
Published: June 2021

The primary physiological mechanism governing concentration of solutes in the renal inner medulla is thought to be the passive permeation of the solutes through tubules. Yet it is recognized that other factors, such as contraction of the renal papilla, contribute to the concentration mechanism. In order to investigate how tubular water transport is affected by pelvic contraction, we developed a computational model based on a realistic three‐dimensional representation of the inner medulla. The advection and diffusion of solutes in the intra‐tubular domains are described in a Lagrangian formulation. The diffusion of solutes at the extra‐tubular domain and the interstitial fluid flow is described in the Eulerian domain. The osmotic effect across the tubule is represented by the radial change of the tubule governed by Darcy's law. Model simulations reveal the potential effects of contraction on concentration gradients in the papilla.
A novel treatment for X‐linked nephrogenic diabetes insipidus: the secret in secretin?
Authors: Procino Giuseppe , Milano Serena , Carmosino Monica , Nicoletti Maria Celeste , Wess Jürgen , Svelto Maria
Published: June 2021

X‐linked nephrogenic diabetes insipidus (NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. V2R inactivation prevents plasma membrane expression of the water channel AQP2 in the kidney collecting duct (CD) cells and impairs the kidney concentration ability.

Here we show that secretin receptor (SCTR) is functionally expressed at the basolateral membrane of the kidney collecting duct cells. Based on this observation, we infused the mouse model of X‐NDI with SCT via osmotic pumps for 14 days at a dose of 2.5 mmol/Kg/day. Interestingly, although the urinary parameters were not altered in SCT‐infused animals, SCT significantly upregulated AQP2 in the intracellular stores of CD principal cells.

As we previously reported that fluvastatin (Flu) treatment increases AQP2 plasma membrane expression in the CD cells of wt mice, SCT‐infused X‐NDI mice received a single injection of Flu (50 mg/Kg). Interestingly, during the following 6 hours of observation, the diuresis of mice treated with SCT+Flu was reduced by nearly 90% and urine osmolality almost doubled. The immunolocalization analysis confirmed that SCT increased AQP2 intracellular stores and Flu injection promoted AQP2 accumulation at the plasma membrane.

Taken together these evidences indicate that the combination of SCT and Flu might represent a novel and effective pharmacological treatment for X‐NDI.
P2Y1‐receptors are expressed by C1 cells and regulate peripheral chemoreceptor modulation of breathing and blood pressure
Authors: Wenker Ian Christopher , Sobrinho Cleyton R , Takakura Anna C , Moreira Thiago S , Mulkey Daniel K
Published: June 2021

Peripheral chemoreception is the crucial brainstem reflex which sense changes in CO2/H+ and/or O2 to adequately match tissue ventilation‐perfusion. However, its cellular and transmitter basis remain unclear. Evidence indicates that peripheral chemoreceptor drive is relayed through the RTN and purinergic signaling in this region can activate cardiorespiratory activity, possibly by a mechanism involving P2Y1‐receptors (P2Y1‐R). Therefore, we used in vivo and in vitro recording techniques to examine the role of P2Y1‐R's expressed by RTN region neurons in peripheral chemoreception. In vivo, unilateral injection of MRS2365 (P2Y1‐ R agonist) into the RTN region of adult rats activated cardiorespiratory responses. Conversely, bilateral application of MRS2179 (P2Y1‐R antagonist) decreased peripheral, but not central, chemoreceptor mediated cardiorespiratory responses, and this was retained during ionotropic glutamate receptor blockade. In vitro (P7–12 rat brain slices), MRS2179 decreased, and MRS2365 increased, action potential firing in non‐chemosensitive neurons, with no effect on chemosensitive neurons. 5 of 10 nonchemosensitive, P2Y1‐expressing neurons filled with biocytin expressed C1 marker tyrosine hydroxylase. Further, DBA‐saporin toxin ablation of C1 cells eliminated MRS2365 responses in vivo. We conclude P2Y1‐R are expressed by C1 cells and contribute to the peripheral chemoreflex.