bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal overconsumption of calories during pregnancy programs offspring for increased adiposity through induction of adipogenic genes
Authors: potu ramesh babu , Arentson Emily J , Ragland Darryl , Donkin Shawn S , Ajuwon Kolapo M
Published: June 2021

Obesity during pregnancy predisposes offspring to metabolic diseases such as obesity and diabetes. Few studies have explored the molecular underpinnings of the increased obesity risk in the offspring. To determine the effects of excessive maternal energy intake on adiposity in the offspring, pregnant Duroc x Landrace gilts were fed either a normal energy (mNE) or high energy diet (mHE) to induce excessive pregnancy weight gain. Offspring were sacrificed at 48h after birth and at weaning (day 21). Expression of adipogenic genes was measured using RT‐PCR. Expression of genes such as PPARγ and CEBPα was not different between mNE and mHE offspring at 48h after birth, but they were induced (P < 0.05) in mHE offspring at weaning. Additionally, SFRP4, SFRP5 and PAI‐1 were induced in mHE offspring at weaning. However, SRC1 expression was higher in mNE offspring at 48h, but not different at weaning (P < 0.05). The expression of PPARγ corepressors, SIRT1 and NCoR1, was elevated (P < 0.05) in mHE offspring at weaning. Therefore, excessive maternal energy intake during gestation programs offspring for increased adiposity through induction of adipogenic transcription factors and suppression of wnt signaling.

Grant Funding Source: Showalter Research Trust
Effect of maternal diet on proliferation and development of rat offspring liver
Authors: Kwon Young Hye , Won Sae Bom , Han Anna
Published: June 2021

Several studies have suggested that nutrition during fetal and neonatal periods may affect liver development and function. We have reported that maternal consumption of either low‐isoflavone soy protein isolate (SPI) or genistein has profound and unique consequences to a programming of lipid metabolism in rat offspring. Therefore, we investigated effects of early life consumption of SPI and genistein on liver proliferation and development. Female rats were fed casein, low‐isoflavone SPI, or casein supplemented with genistein diet for two weeks before mating and throughout pregnancy and lactation. Male offspring were studied at 21 d after birth (CAS, SPI, and GEN groups). As determined by proliferation cell nuclear antigen protein and H19 mRNA levels, hepatic proliferation was higher in SPI group compared to CAS and GEN groups, which may contribute to increased relative liver weights. Consistently, we observed an increased activation of beta‐catenin pathway in SPI group. There was no difference in apoptosis among groups. Serum homocysteine levels were higher, and betaine‐homocysteine S‐methyltransferase and glycine N‐methyltransferase mRNA levels were lower in SPI group than those in CAS and GEN groups, suggesting that one‐carbon metabolism may be involved in maternal dietary regulation of liver proliferation and development in offspring. This work was supported by National Research Foundation of Korea.
Fructose‐induced stress signaling in hepatocytes involves methylglyoxal
Authors: Wang Dong , Wei Yuren , Pagliassotti Michael
Published: June 2021

Fructose produces hepatic insulin resistance in humans and animals. We have proposed that the selective metabolism of fructose by the liver and the unique ability of fructose‐1‐phosphate to stimulate hepatic glucose uptake can, under conditions of elevated fructose delivery, inflict a metabolic insult that is localized to the hepatocyte. The present study was designed to identify potential cellular effectors of this insult. Primary hepatocytes were incubated with 8 mM glucose and 0.12% inulin (G, n=6) or 8 mM glucose, 0.12% inulin, and 28 mU of inulinase (GF, n=6) in the presence or absence of insulin for 0, 2, or 4h. GF produced fructose concentrations of ~0.7 mM over the 4h experiment. GF induced phosphorylation of MKK7 and JNK, phosphorylation of serine307 on IRS‐1, and reduced tyrosine phosphorylation of IRS‐1 and ‐2. GF increased ceramide levels and reactive oxygen species (ROS); however inhibitors of ceramide synthesis or ROS accumulation did not prevent GF‐mediated changes in MKK7, JNK or IRS proteins. Low concentrations of methylglyoxal recapitulated the GF‐induced changes in MKK7, JNK and IRS proteins. We hypothesize that GF‐mediated changes in stress signaling involves methylglyoxal in primary hepatocytes.
Development of diet induced obesity models in rats, comparison of metabolic and genetic effects
Authors: Hamdan-Perez Nashla , Torres Nimbe , Palacio Armando Tovar , Ordaz-Nava Guillermo , Torre-Villalvazo Ivan , Moran Sofia , Tovar-Palacio Claudia , Martinez Braulio , Hiriart Marcia , Santillan-Medina Roberto , Torres-Villalobos Gonzalo
Published: June 2021

The development of dietary obesity models in rats mimicking human obesity may help understanding its pathology and to evaluate new therapeutic strategies for treatment. We fed male Wistar rats either with a control chow diet (C), a 45%Kcal lard diet + 5% sucrose in water (LS) a chow diet +50%Kcal lard + 5% sucrose in water (CLS) or a chow diet + 20% sucrose in water (CS) for 22 weeks (W). At the end of study LS and CS diets increased hepatic and serum triglycerides, and these differences were found in CS diet since w 4. Hepatic SREBP‐1 mRNA was higher in LS and CS but FAS mRNA only increased in CS group. The oral glucose tolerance test (OGTT) at 18 W revealed that rats fed LS, CLS and CS developed insulin resistance. Body weight was 29% higher in rats fed LS than the rest of the groups due to increased adipose tissue (AT) mass. Subcutaneous (S) and visceral (V) AT was increased 3 fold in LS with respect to C, 2 fold with respect to CLS and 75% with respect to CS. HSL, perilipin and PPAR gamma mRNA was higher in SAT of LS and CS rats, whether in VAT those genes increased only in CS and CLS. CS diet increased 3 fold the glomerular filtration rate. In conclusion this study demonstrates than the fat and carbohydrate content of the diet differentially induces obesity and comorbidities.

Grant Funding Source: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Genetic variation in the epithelial sodium channel (ENaC) and salt taste perception in humans
Authors: Dias Andre Gautam , El-Sohemy Ahmed
Published: June 2021

Despite individual differences in salt taste sensitivity no studies have identified variations in genes that explain this variability. Our objective was to determine whether single nucleotide polymorphisms (SNPs) in the epithelial sodium channel (ENaC), a putative salt taste receptor with 3 subunits, modifies salt (NaCl) taste in men (n=28) and women (n=67) aged 20–35 yrs. Taste thresholds (TT) were determined using a 3 alternative forced choice staircase model with solutions ranging from 9 ×10−6 to 0.5 mol/L. Suprathreshold taste sensitivity (STT) to 5 solutions (0.01–1 mol/L) was assessed using a general Labeled Magnitude Scale. Genotypes were extracted from an Affymetrix 6.0 chip (5 SNPs in SCNN1A; 34 SNPs in SCNN1B; 13 SNPs in SCNN1G). A general linear model was used to compute differences between genotypes. No SNPs in the SCNN1A or SCNN1G genes modified salt taste. In the SCNN1B gene the rs9939129 (C>T) SNP modified TT (mmol/L ± SE) where carriers of the T allele detected significantly lower NaCl concentrations than CC homozygotes (2.33±0.76 vs 3.85±0.37, p=0.02). The rs239345 (A>T) SNP in this gene modified STT (iAUC ± SE) were those homozygous for the A allele perceived salt solutions less intensely than carriers of the T allele (70.82±12.16 vs. 96.95±3.75, p=0.02). Our findings indicate that variation in the SCNN1B gene modifies salt taste perception in humans.

Grant Funding Source : The Advanced Food and Materials Network
Effect of caloric restriction on the expression of the Sirtuin Proteins
Authors: Nguyen Kinh-Vy , Rickert Emily L , Olefsky Jerrold M , Webster Nicholas J
Published: June 2021

SirT1 is a deacetylase whose expression and activity increases during times of caloric restriction (CR). CR has been implicated lifespan extension in rodents, flies and worms, and SirT1 appears to be required for this increased longevity. Sirtuins have also been implicated in the regulation of transcriptional events, apoptosis, and energy efficiency. Many of the sirtuin proteins are similar in function, although they vary in cellular location. Interestingly, numerous studies demonstrated SirT1 activity during CR, but CR effects on the remaining six sirtuin proteins remains relatively unknown. This study aims to analyze the expression of sirtuins in a variety of tissues from mice subjected to a two week 60% CR. We hypothesize that CR will cause increases in mRNA levels of multiple sirtuins. Male and female mice were monitored daily to determine their individual food intake for two weeks and were then given 60% of their normal daily intake for two weeks. Animals were euthanized and tissues snap frozen and stored until further processing. We will present data showing the levels of SirT1–7 as well as other important metabolic and reproductive genes in response to CR. This work is supported by NIH grants U54 HD012303 and T32 DK007494.
Relation between plasma vitamin K and bone and cartilage markers in osteoarthritic dogs
Authors: Mani Anna Salas , Manuelian Menchu , Font Josep , Totusaus Xavier , Vermeer Cees , Vilaseca Lluis , Torre Celina
Published: June 2021

Vitamin K is a cofactor in the activation of some proteins related to bone and cartilage homeostasis: osteocalcin (OC) is involved in bone formation, while matrix Gla protein (MGP) inhibits endothelium and cartilage calcification. Thirty three osteoarthritic dogs (OA) and 30 healthy dogs (C) were blood sampled to analyze vitamin K forms (K1, K2: MK4, MK6, MK7) and markers of bone and cartilage metabolism (OC, NTX, BAP, carboxylated MGP (cMGP), uncarboxylated MGP (ucMGP), CPII). Data was divided into 2 populations: high plasma vitamin K (HK>1ng/ml, N=34), low plasma vitamin K (LK<1ng/ml, N=29). Total OC levels in OA dogs were higher than in C dogs (C:1.6±0.3 vs OA:2.3±0.3). This difference was also observed in HK dogs, but not in LK dogs. There was a trend to higher BAP levels in HK vs LK dogs (HK:22.6±4.4 vs LK:15.2±1.4), while LK dogs tended to have higher levels of ucMGP than HK (HK:9.1±3.3 vs LK:21.5±5.2). In LK dogs, total K and K2 levels were correlated with the ratio ucMGP/cMGP (UCR) (K2‐UCR: r=−0.359; total K‐UCR: r=−0.416). In HK this correlation was not present, although in the global population, correlation was still trendy for K2 (UCR: r=−0.213). High levels of plasma vitamin K could help maintain higher remodeling bone activity in dogs with altered joint metabolism, which has been associated with a reduced cartilage loss. Increasing plasma vitamin K levels could contribute to the activation of inhibitory calcification proteins (MGP), which may be helpful in osteoarthritis. Source of research support: Affinity Petcare.
Maternal Vitamin D Supplementation Results in Higher Expression of Bone Formation Markers at the Growth Plate and Site Specific Effects on Bone Strength in Male Offspring
Authors: Fielding Kristina A , Chen Jianmin , Jahani Raha , Comelli Elena M , Ward Wendy E
Published: June 2021

Lower maternal serum 25‐hydroxyvitamin D or ultraviolet B exposure is associated with lower bone mineral in offspring during childhood. The effect of higher maternal vitamin D status on offspring bone health at adulthood is less clear. Using the CD‐1 mouse model, this study determined if dams fed supplemental (5,000 IU/kg diet) versus low (25 IU/kg diet) levels of vitamin D during pregnancy and lactation affected bone health of male offspring. At weaning, expression of osterix, osteoprotegrin, RANKL and vitamin D receptor (VDR) in the tibia growth plate was measured by immunohistochemical analyses in a subset of male mice (n=8/group). Some offspring were fed their mothers diet or the opposite diet (n=14/group) until age 3 months when bone strength, i.e. peak load, at lumbar vertebra and femur neck and midpoint was measured. At weaning, mice exposed to supplemental vitamin D had higher (p<0.05) expression of osteoprotegrin and osterix and lower (p<0.05) expression of VDR with no difference in expression of RANKL in proliferating or hypertrophic chondrocytes in the tibia growth plate. At 3 months of age, offspring of mothers fed supplemental vitamin D had lower (p<0.05) femur neck peak load with no difference in peak load at other skeletal sites regardless of post‐weaning diet. Further study is required to understand the structural changes that contribute to the lower femur neck peak load.
BACTERIAL STRAIN‐SPECIFIC EFFECTS ON IMMUNE MARKERS IN RSV INFECTED MICE
Authors: mitmesser susan hazels , Russell William Michael , O'Mahony David , MacSharry John , Ceddia Michael , O'Mahony Liam
Published: June 2021

Background

Respiratory syncytial virus (RSV) causes respiratory tract infections in infants and immunocompromised individuals and has been associated with the development of asthma.

Objective

To evaluate the effect of feeding Bifidobacterium longum AH1206, Bifidobacterium breve AH1205, and Lactobacillus salivarius AH102 to RSV infected mice.

Methods

BALB/c mice (N=10/group) were fed 109 cfu/day B. longum AH1206, B. breve AH1205, or L. salivarius AH102 for 21 days. On day 14, mice were nasally challenged with RSV. Following infection, mice were weighed and clinically scored daily. On day 21, lungs were harvested for RSV quantification and gene expression analysis of several immune biomarkers. Infected and non‐infected, placebo fed groups served as positive (RSV+) and negative (RSV‐) controls, respectively. Mann‐Whitney t‐test was used to determine statistical differences, p<0.05.

Results

All RSV infected mice had increases in clinical scores and lost weight post‐infection with no differences among groups. There were no differences in RSV titres or cytokine gene expression among treatments. Compared to the RSV+ control, the AH102 group showed a significantly lower increase in Foxp3 expression (p<0.05). AH1206 showed significant increases in CD86, CD127 and CD11c expression compared to the RSV‐ and RSV+ controls (all p<0.01), AH 1206 also showed a significant increase in CD3 expression compared to RSV‐ (p<0.001).

Conclusion

Strain‐specific differences were observed in a number of immune cell markers that could play an important role in enhancing clearance and immunity to RSV infection. The clinical relevance of these findings should be the subject of further studies.
EARLIER KIDNEY INJURY ASSOSSIATED WITH HIGH FAT DIET FROM WEANING TO ADULT RATS
Authors: de Oliveira Leite Ana Paula , Muller Cynthia Rodrigues , Senger Nathalia , Americo Anna Laura Viacava , Mateus Raquel Sarmento , Fonteles Manasses Claudino , Farah Vera , Fiorino Patricia
Published: June 2021

The aim of this study was to evaluate the effect of administration of a high fat diet after weaning, during 8 weeks, in renal morphology and metabolic profile. Weaned male Wistar rats (21 days, n=8/group) were randomized divided in Control group (CG), commercial rat feeding, and Hyperlipidic group (HG) by addition of 30% unsalted butter in commercial diet to rats during 8 weeks. The left kidney was collected under anesthesia (sodium pentobarbital, 50mg/kg) to histological glomerular analysis (5μm thick, Picrosirius Red) to evaluate Glomerular Tuft Area (GTA) and Bowman's Capsule Area(BCA). Blood was collected to biochemical assays: basal glycemia, triglycerides and total cholesterol using the enzymatic colorimetric kits (Labtest, BR). There was no change in basal glycemia (CG: 92 ± 4 vs HG: 85±4 mg/dL). However, HG showed an increase in Triglycerides (CG: 51 ±5 vs HG: 78±6 mg/dL) and Total Cholesterol (CG: 75 ±4 vs HG: 101±10 mg/dL). There was an important reduction in GTA (26%) and in the BCA (22%) in HG group. At the end of the protocol, we did not find differences in bodyweight between the groups, however, the adiposity was increased in HG (15 ±1g) when compared with CG (5.2±0.5 g). These data suggest high fat diet during lifespan induced metabolic alterations associated with earlier kidney injury. Supported By: Mackpesquisa (059/2011).
The effect of dietary selenium intake on numbers of T and B cells in C57BL/6 mice with chronic inflammation
Authors: Nekatebeb Hana , Smith Brenda J , Kuvibidila Solo , Wang Yan , Girma Abiy , Peterson Sandra , Stoecker Barbara J
Published: June 2021

Selenium (Se) as a nutrient has many beneficial functions related to its nutritional, biochemical and molecular properties. Se is important for adequate immune response. In this study dams were fed a Torula yeast Se depletion diet for the final week of gestation and through lactation. At 23 days, 47 pups were weaned to the depletion diet or to diets with 0.2, 2 or 4 mg/kg diet Se added as sodium selenate for 14 weeks. Four weeks before necropsy lipopolysaccharide (LPS) time‐release pellets (0 or 0.1μg/g body weight/d) pellets were implanted subcutaneously. At necropsy the bone marrow from femur was flushed with saline, labeled with fluorochrome conjugated primary antibodies (CD3, B220, and CD4) and analyzed by flow cytometry (FACS). LPS stimulation versus placebo increased numbers of T helper cells (1.7×106 vs 0.93×106), T cells (0.57×106 vs 0.31×106) and B cells (3.3×106 vs 2.5×106). In addition CD3+ cell numbers were greater with increasing Se intake (p<0.03). Although the immune system is dependent upon production of oxidative molecules as a protection against microbial pathogens, benefits of Se also include protection from excessive damage by oxidative radicals. Further understanding of the mechanisms by which dietary Se affects these immune cell populations will contribute to knowledge of using Se supplementation to affect T cell mediated immune response. (Supported by Oklahoma Center for Advancement of Science & Technology)
Effect of conjugated linoleic acid on fatty acid synthesis in soy and coconut oil fed mice
Authors: Sanda Milo W , Angius Zachary , Ippagunta Siri M , Barnes Kimberly M
Published: June 2021

Dietary conjugated linoleic acid (CLA) causes a body fat loss, which is enhanced when mice are fed coconut oil (CO), in part due to increased lipolysis. Our objective was to determine the effect of CLA supplementation on the mRNA expression of genes involved in fatty acid synthesis in mice fed soy oil (SO) or CO. Male mice (ICR; n=80; 3 wk‐old) were fed 7% SO or CO diets for 6wk, then 0 or 0.5% CLA for 3,7,10, or 14d. The liver relative mRNA expression of Fatty Acid Synthase (FAS), Acetyl‐CoA Carboxylase (ACC), Malic Enzyme (ME), Sterol Regulatory Element Binding Protein (SREBP), and Stearoyl‐CoA Desaturase (SCD) were determined via real time RT‐PCR and normalized to Acidic Ribosomal Protein. FAS enzyme activity was also determined as NADPH disappearance. CO increased the expression of ME (P < 0.01), FAS (P < 0.001), and SCD (P < 0.001) but decreased the expression of ACC (P < 0.01). CLA increased the expression of ME (P < 0.001). Specifically, the CO+CLA‐fed mice had increased (P < 0.05) ME and SCD mRNA and decreased (P < 0.05) ACC mRNA vs all other diet groups. There was also an effect of day on SCD mRNA, where SCD expression increased (P < 0.01) with increasing days on feed. SREBP mRNA and FAS enzyme activity were not different. It appears that CO‐feeding may cause an increase in fatty acid turnover that could contribute to the greater loss of body fat observed when these mice are fed CLA.
Effect of genetics and feeding strategies on growth of rainbow trout
Authors: Berg Levi E , Gatrell Stephanie K , Cleveland Beth M , Grimmett Juanita G , Leeds Tim , Weber Greg , Klandorf Hillar , Turk Philip , Semmens Kenneth J , Blemings Kenneth P
Published: June 2021

To study the influence of genetics and feeding strategy, we measured growth and mRNA expression of protein degradation markers in growth‐selected and control rainbow trout that were either fed to satiation or limit‐fed. Fish were limit fed to 90–95% of the feed required to reach maximal growth. Length and weight of 1600 trout were measured every six weeks for 24 weeks. After 24 weeks of dietary treatment there was an interaction (p<0.05) between genetics and feeding strategy for both length and weight. The least squares means ± the standard error of the means for weight of satiation/control, limit‐fed/control, satiation/selected and limit‐fed/selected fish were 371 ± 6, 350 ± 4, 544 ± 24, and 426 ± 16 grams and for length 299 ± 2, 291 ± 2, 347 ± 2 and 330 ± 2 mm, respectively. mRNA expression of 4 components of the ubiquitin/proteasome machinery were decreased (p<0.05) by an average of 17% in muscle of the growth‐selected fish consistent with a reduced capacity to degrade protein. No effect of feeding strategy was seen for mRNA expression nor was an interaction detected. No differences in IGF‐1 concentrations were detected due to feeding strategy or genetics. This suggests decreased degradation of protein through proteasomes and caspases could be the cause for increased weight and length of the growth‐selected trout. Support: Aquaculture Product and Marketing Development Project.
The chronic effect of quercetin and epigallocatechin gallate based supplementation on exercise performance in mice
Authors: Kennerly Krista , Knab Amy , Kam Lynn , Henson Dru , Meaney Mary Pat , Nieman David
Published: June 2021

This study attempted to determine the optimal dose and combination of quercetin (Q) and epigallocatechin gallate enriched green tea extract (EGCG) required to optimize performance during consecutive days of exercise in mice. C57BL/6J mice (n=176) were randomly assigned to one of five groups: control, 6.25 mg Q/kg and 1.25 mg EGCG/kg (Q/EGCG low), 12.5 mg Q/kg and 2.5 mg EGCG/kg (Q/EGCG mid), 25 mg Q/kg and 5 mg EGCG/kg (Q/EGCG high), and 25 mg Q/kg (Q). Mice were supplemented for 3, 7, and 14 days (n=12 animals per group). For the last three days of the dosing cycle mice were run on a treadmill at 14m/min for up to 2.5 hours. Total run time over the three‐day period of exercise only differed between groups after 14 day supplementation (F=2.48, P=0.043), with significant differences between the control group and Q/EGCG low and mid. In conclusion, 14 day chronic ingestion of quercetin in combination with EGCG at mid and low relative concentrations was required to improve performance time in exercising mice.
Associations between Preterm Birth, Small For Gestational Age, and Early Neonatal Morbidity, and Cognitive Function in School‐Age Children
Authors: Christian Parul , Murray-Kolb Laura , Katz Joanne , Tielsch James , Schaefer Barbara , Cole Pamela , LeClerq Steven , Khatry Subarna K.
Published: June 2021

The long term consequences of preterm, small for gestational age (SGA, defined as birth weight for given gestational age less than the 10th percentile of the reference), and early newborn morbidity on functional outcomes are not well described. In rural Nepal, we assessed children (n~1900) at 7–9 y of age, for whom these exposures were available at birth. The prevalence of low birth weight (LBW), preterm, and SGA was 40%, 21%, and 55%, respectively, whereas symptoms of birth asphyxia and sepsis were reported in 7% and 9% of children. At follow‐up they were tested on aspects of intellectual, executive, and motor function. In multivariable regression analyses, low birth weight was strongly associated with scores on the Universal Nonverbal Intelligence Test (UNIT), tests of executive function, and the Movement Assessment Battery for Children (MABC). However, of the two underlying causes of LBW, preterm was not associated with any of the test scores. However, SGA was significantly associated with lower UNIT scores (−1.9 SD=0.4); higher proportion failure on the Stroop test (0.06, SD=0.02); and lower scores on the backward digit span test (−0.14, SD=0.04), MABC (0.94, SD=0.27), and finger tapping test (−0.63, SD=0.23) (all p<0.005). Neither birth asphyxia nor sepsis symptoms were significantly associated with the outcomes.

Support: NICHD, Gates Foundation.
Infant and young child feeding (IYCF) practices:A formative research in rural India
Authors: anwar fahmina , Srivastava Ratan , Singh S
Published: June 2021

Exclusive Breastfeeding (EBF) & thereafter adequate complementary feeding (CF) are two important preventive interventions against child mortality. To intervene these areas, Formative research was carried out to improve Infant and young child feeding (IYCF) practises among mother & child pair of 0–6 & 7–24 months of age, in rural India. Study was conducted in 3 phases over a period of 4 months 1. Assesment: 6 Focused group discussions (FGDs) among mothers & chid pair of 0–6 & 7–24 months, 5 In‐depth interviews of Health workers & base line survey of the study village was conducted to asses perceptions & practices regarding IYCF & also to identify mothers of 0–6 & 7–24 months child. 2. egotiation: Participatory Trail for improved practices (TIPs) counselling guide with recommended practices was prepared & used to explore if mothers could try new practices & continue using them. 30 mother and child pair in each 0–6 & 7–24 months group (n =60) were selected & TIPs was tried for a period of 15 days. 3. Evaluation: To see whether new recommendations was implemented or not & what were motivating factors/barrier for same. Study revealed suboptimal IYCF practices, such as low rates of EBF, early introduction of nutrient‐poor gruels and delay in introduction of adequate CF. TIPs showed, mothers are willing to adopt new feeding practices and can increase the amount of energy & essential micronutrients like vitamin A, iron, zinc & carotene.

Grant Funding Source: University Grant Commission
Breastfeeding practices and beliefs among HIV+ pregnant and lactating women on antiretroviral therapy in rural Uganda indicate obstacles to following national guidelines
Authors: Natamba Barnabas Kahiira , Robine Marion , Luwedde Flavia , Mwesigwa Julia , Natureeba Paul , Osterbauer Beth , Ades Veronica , Clark Tamara , Charlebois Edwin , Plenty Albert , Havlir Diane , Cohan Deborah , Achan Jane , Young Sera
Published: June 2021

Ugandan guidelines recommend 6 months of exclusive breastfeeding (EBF) for HIV‐infected women on antiretroviral therapy (ART), with continued breastfeeding (BF) for at least 1 year. We explored infant feeding (IF) practices and beliefs among HIV‐infected pregnant and BF women on ART in the PROMOTE trial (NCT00993031) in Tororo, Uganda. IF practices were determined using monthly maternal reports from a prospective cohort of 219 PROMOTE infants born between March 6, 2010 and October 31, 2011 and compared to 2007 Ugandan Demographic and Health Survey (DHS) data. To assess IF beliefs, a purposive sample of 24 pregnant and 32 BF PROMOTE participants took part in in‐depth interviews (IDIs) in July and August 2011 (n=56). In the PROMOTE study, the prevalence of EBF was 90.4% and 71.6% at 3 and 6 months, vs. 64.8% and 10.8% respectively in the DHS. In contrast, the prevalence of BF at 12 months was 62.6% in PROMOTE vs. 88.3% in DHS. IDIs revealed several potential reasons for suboptimal IF: 64.3% believed that HIV was an important reason to avoid BF and 21.4% did not know the recommended duration of EBF. Of BF IDI participants, 78.1% were concerned about adequate breast milk production and 46.9% had actually experienced problems with EBF, e.g. unsatisfied baby. Among all IDI participants, 96.4% desired further IF education. Further research is needed to understand optimal support to overcome identified obstacles to BF among HIV+ women in rural Uganda.

Grant Funding Source: National Institute of Child Health and Human Development
A Dietary Analysis of Haitian Infants and a Critical Analysis of Dietary Quality Using IYCF Standards
Authors: Webster Lauren Elizabeth , Heidkamp Rebecca , Stoltzfus Rebecca , Fitzgerald Daniel , Pape Jean William
Published: June 2021

The 2008 Lancet Series on Maternal and Child Undernutrition identifies infant feeding education with food supplementation as an effective strategy to reduce child undernutrition by improving overall nutrient intake. We assessed the impact of an intervention providing infant feeding education and a lipid‐based nutrient supplement (LNS) on the overall dietary quality of non‐breastfed HIV‐exposed uninfected infants in urban Haiti. Dietary intake data was collected in intervention (n=77) and control (n=36) infants at age 9 mo using 24‐hr recalls with caregivers. Diet quality was assessed using the WHO Infant and Young Child Feeding (IYCF) indicators. Intervention participants were more likely to meet the minimum dietary diversity indicator compared to the control group both with (63.6% vs 33.3%, p=0.003) and without (53.9% vs 33.3%, p=0.048) including the contribution of the LNS to the diet. In addition, intervention infants were more likely to consume iron‐rich foods only when the LNS was included in the analysis (89.5% vs 69.4%, p=0.008). Though differences in the infants’ diets do exist with and without the lipid‐based supplementation, findings suggest that both of the intervention components (education and LNS) improved the infant diets. Research support was provided by the Weill Cornell Center for Global Health.
Role of private institutions in the globalization of medical education
Authors: Tulp Orien L , Einstein George P , Karam David , Bailey R Keith , Robinson Bruce H , Martinez Julio , Hudson Perry B
Published: June 2021

In the past century, the world has witnessed the greatest increase in its population in history due to combined effects of scientific advances in medical care, greater longevity, global progress in, and other factors including a global Green Revolution and the associated benefits to agricultural productivity and a globalized food supply. The number of provider health care professionals, including physicians, nurses, and other practitioners, however, has consistently failed to keep pace with the expanding global population during this period, and has placed a strain on medical resources in the USA and many other Nations. To address the need for expansion in medical education, the further development of venues in private medical education is inevitable. Historically, much of the financial burden for professional medical education has been tied to heavily strained public sector financial support, which has limited the ability of public sector Institutions to expand in concert with the population demographics, and which sector has trailed the population trends for several decades. To this end, privately funded educational Institutions now share an increasingly greater role in development of innovative solutions to increasing the numbers of healthcare professionals worldwide, and thus ameliorating the existing progressive strain on the resources of traditional academic institutions. Institutional support.
Mucosal permeability is an intrinsic factor determining susceptibility to dextran sulfate sodium‐induced colitis in rats
Authors: Iwaya Hitoshi , Maeta Koushi , Hara Hiroshi , Ishizuka Satoshi
Published: June 2021

We investigated the differences in the pathogenesis of dextran sulfate sodium (DSS)‐induced colitis between two inbred rat strains, WKAH and DA rats, to determine an intrinsic factor responsible for the development of colitis. The body weight reduction, stool consistency, and rectal bleeding were daily evaluated during DSS treatment period. The clinical symptoms in DA rats were significantly severer than that in WKAH rats. In an early phase of DSS treatment period, we measured the expressions of cytokine mRNA and tight junction (TJ) proteins in the colonic mucosae. DSS treatment increased prominently the mRNA expression levels of TNF‐α, IL‐12 p35, and IL‐23 p19 in the DA rat. A colonic permeability was greater in the DA rats than in the WKAH rat. Higher expression of claudin‐4 and Junctional adhesion molecule (JAM)‐A proteins were observed in the DA rats than that in the WKAH rats without DSS conditions. The different expression pattern of TJ proteins probably determines the colonic permeability of rats. However, DSS treatment enhanced TNF‐α production in mesenteric leukocytes isolated from the WKAH rats rather than that from DA rats, suggesting that the response of immune cells to DSS in the DA rats was weaker than that of the WKAH rats. In conclusion, the intrinsic colonic permeability is one of critical factors responsible for the susceptibility to colitis.
Loss of α SNAP induces colonic epithelial cell apoptosis via down‐regulation of Bcl‐2 expression and fragmentation of the Golgi
Authors: Naydenov Nayden G , Harris Gianni , Brown Bryan , Schaefer Katherine L , Dash Swadesh K , Fisher Paul B , Ivanov Andrei I
Published: June 2021

Intracellular trafficking is a key mechanism that regulates cell fate by participating in pro‐death or pro‐survival signaling. A soluble N‐ethylmaleimide sensitive factor (NSF) attachment protein alpha (αSNAP) is well‐known component of vesicle trafficking machinery. αSNAP increases cell resistance to cytotoxic stimuli, although mechanisms of its pro‐survival function remain poorly understood. In this study, we found that either siRNA‐mediated knockdown, or overexpression of dominat negative form of αSNAP induced apoptosis in several types of epithelial cells. This apoptosis was not caused by activation of the major pro‐death regulators Bax and p53 and was independent of a key αSNAP binding partner, NSF. Instead, death of αSNAP‐depleted cells was accompanied by down‐regulation of the anti‐apoptotic Bcl‐2 protein; it was mimicked by inhibition and attenuated by overexpression of Bcl‐2. αSNAP depletion resulted in impaired Endoplasmic Reticulum (ER) to Golgi trafficking and Golgi fragmentation. Furthermore, pharmacological disruption of Golgi/ER with brefeldin A and eeyarestatin or depletion of ER‐Golgi associated AAA‐ATPase p97 decreased Bcl‐2 level and triggered cell apoptosis. These results reveal a novel role for αSNAP in regulating epithelial cell survival. Supported by NIH grants DK083968 and DK084953 to AII.
Quantifying differences in local wall stress between carotid and femoral arteries
Authors: Wang Roy , Gleason Rudy L , Brewster Luke Packard
Published: June 2021

Objective

Arterial remodeling after vascular procedures are mediated by pulsatile stress, but arterial wall biomechanics likely contribute; this study defines differences in arterial wall stress between healthy femoral and carotid arteries.

Method

Healthy nonhuman primate arteries were tested on a custom‐made device to determine biaxial mechanical responses. A custom LABVIEW program was using for data acquisition and processing. Local wall stress was calculated based on a nonlinear, finite deformation framework utilizing an orthotropic material model. Residual stresses were considered in the analysis through quantifying circumferential and longitudinal opening angles. Heteroscedastic t‐tests were used to analyze the results.

Results

The pressure‐diameter response of the arteries at the in vivo stretch demonstrate that femoral are stiffer than the carotid arteries (P=0.05); Fig. 1. Circumferential opening angle results (Fig. 2) also show a trend toward a greater opening angle in the femoral arteries (P=0.3).

Conclusions

These results support baseline biomechanical differences between femoral and carotid arteries in nonhuman primates. A better understanding of the matricellular differences between arteries may provide improved compatibility strategies for future therapies.

(RLG:GTEC Foundation Endowment; NIH, NSF)
A composite polymeric nanoparticle overcomes multidrug resistance and ameliorates doxorubicin‐associated cardiomyopathy
Authors: Campbell Nathaniel R , Pramanik D. , Das S. , Gupta S. , Chenna V. , Bisht S. , Shah P. Sysa , Bedja D. , Karikari C. , Steenbergen C. , Gabrielson K. L. , Maitra Am. , Maitra An.
Published: June 2021

Resistance to chemotherapeutic drugs, and in particular multidrug resistance (MDR), is a major impediment to a successful chemotherapeutic regimen, with the use of doxorubicin (DOX) limited both by MDR and severe side effects including cardiotoxicity. Curcumin has been shown to ameliorate both DOX resistance and cardiotoxicity; however, its use is limited by extremely low bioavailability. Building upon our recently developed NanoCurc™ (NC) formulation that significantly enhances the bioavailability of curcumin, we synthesized a doxorubicin‐curcumin multidrug nanoparticle formulation called NanoDoxCurc (NDC) towards overcoming both MDR and DOX‐induced cardiotoxicity. NDC significantly inhibited MDR function and provided almost complete growth inhibition both in vitro and in vivo in models of several DOX‐resistant cancers. In a model of cumulative dose toxicity, both NDC and the single agent NanoDox (ND) showed drastically improved toxicity profiles compared to DOX and Doxil® as evaluated by mouse echocardiography and hematological parameters. This improvement was achieved through a reduction of DOX‐induced oxidative stress in NDC‐ and ND‐treated mice. Such a composite DOX‐curcumin nanoparticle that both overcomes MDR‐based DOX resistance and DOX‐induced cardiotoxicity holds great promise for providing lasting and safe therapy. Supported by NIH 5U54CA151838‐02.
Expression of receptor activator of nuclear factor‐κB (RANK), RANK ligand, and osteoprotegerin in the normal and E. coli lipopolysaccharide‐treated horse lungs
Authors: Channabasappa Shankaramurthy , Singh Swaran , Singh Baljit
Published: June 2021

Receptor activator of nuclear factor‐κB ligand (RANKL), its receptor RANK and antagonist osteoprotegerin (OPG) are members of the TNF receptor superfamily. RANKL/RANK signaling mediates TNFα‐induced inflammation and RANKL acts as a chemoattractant for immune cells. OPG interacts with and blocks RANKL signal transduction. There are no or little data on the expression of RANKL, RANK, and OPG in normal or inflamed lungs. Therefore, we studied their expression in control and lipopolysaccharide (LPS) treated horse lungs. Immunohistochemistry showed RANKL expression in alveolar/septal macrophages, vascular endothelium, and alveolar septum but not in airway epithelium in control horses. The LPS treatment increased RANKL expression in airway epithelium and alveolar septum. While a weak staining for RANK was detected in airway epithelium and vascular endothelium of control horse lungs, the expression was increased in airway epithelium of LPS‐treated horses. OPG was expressed in airway epithelium and alveolar/septal macrophages and was increased in LPS‐treated lungs. Immunoelectron microscopy detected all three molecules in pulmonary intravascular and alveolar macrophages. Western blot confirmed expression of all three molecules in the lungs. These data show LPS‐induced changes in the expression of RANK, RANKL, and OPG to suggest their roles in endotoxin‐induced lung inflammation.

Grant Funding Source: NSERC
Effects of 5‐HT2A receptor antagonism on cocaine self‐administration, cocaine‐induced reinstatement, and cocaine‐induced dopamine overflow in rhesus monkeys
Authors: Winschel Jake Edward , Murnane Kevin Sean , Stewart Shaya , Howell Leonard Lee
Published: June 2021

Growing evidence indicates that serotonin (5‐HT) systems modulate the effects of drugs that affect dopamine systems, particularly via the 5‐HT2A and 5‐HT2C receptors. For example, 5‐HT2A receptor antagonists have been shown to inhibit various neurochemical and behavioral effects of stimulants, primarily in rodents. Using a within‐subjects design in rhesus macaques (n=3), we evaluated the effects of the selective 5‐HT2A antagonist M100907 on IV cocaine self‐administration and cocaine‐primed reinstatement. In separate subjects (n=4), we evaluated the role of 5‐HT2A receptors in cocaine‐induced dopamine overflow using in vivo microdialysis targeting the nucleus accumbens. Consistent with previous studies, at 0.3 mg/kg, M100907 did not robustly ablate cocaine self‐administration, even over a three day dosing regimen. In contrast, but also consistent with previous studies, 0.3 mg/kg M100907 largely abolished cocaine‐primed reinstatement across a range of cocaine priming doses. In accord with its lack of effect on cocaine self‐administration, M100907 did not significantly attenuate cocaine‐induced dopamine overflow in the nucleus accumbens. As reinstatement procedures are the most widely accepted preclinical model of drug relapse, these findings suggest that 5‐HT2A receptor antagonism may be a viable approach to relapse prevention in cocaine‐dependent subjects. Supported by DA00517 and RR00165.
Can the Stereotypy‐Inducing Effects of Atypical Dopamine Uptake Inhibitors Account for Their Blockade of Cocaine Self Administration?
Authors: Hiranita Takato , Li Libin , Hayashi Shuichiro , Cao Jianjing , Newman Amy H. , Katz Jonathan L.
Published: June 2021

Several N‐substituted benztropine (BZT) analogs with high dopamine transporter (DAT) affinity decreased cocaine (Coc) self‐administration (SA) relative to food‐maintained behavior in rats. Further these BZT analogs failed to increase rates of responding greater than saline injections, when substituted for Coc (JPET:329;677). The present study examined if BZT analogs enhance the stereotypy‐inducing effects of Coc, which in turn interferes with continued Coc SA. Standard DAT inhibitors (WIN35,428, methylphenidate) maintained responding greater than saline injections when substituted for Coc, whereas responding maintained by BZT analogs (AHN1‐055, AHN2‐005, JHW007, JHW013, GA1‐69, GA2‐50, GA2‐99) was not different from vehicle. Additionally the DAT inhibitors shifted the Coc SA dose‐effect curve leftward, whereas the BZT analogs dose‐dependently decreased maximum SA of Coc SA. Administered alone, standard DAT inhibitors like Coc dose‐dependently increased stereotypy and enhanced the stereotypy‐induction produced by Coc. The BZT analogs, however, were inactive alone and did not significantly change the effects of Coc. Thus it appears that the induction of stereotypy does not account for the decreases in Coc SA produced by BZT analogs. The present study further supports the development of N‐substituted BZT analogs as medications to treat Coc abuse. Supported by NIDA IRP.
Tolerance and cross‐tolerance produced by delta‐9‐tetrahydrocannabinol treatment in rhesus monkeys
Authors: Hruba Lenka , Ginsburg Brett C. , McMahon Lance R.
Published: June 2021

The present study used a drug discrimination procedure to test the hypothesis that the magnitude of tolerance/cross‐tolerance produced by delta‐9‐tetrahydrocannabinol (delta‐9‐THC) treatment varies inversely with the relative cannabinoid agonist efficacy of test compounds. Five rhesus monkeys discriminated 0.1 mg/kg i.v. delta‐9‐THC from vehicle. Sensitivity to cannabinoid agonists (delta‐9‐THC, CP 55940, JWH‐018 and JWH‐073) was determined before and after 3 or 14 days of delta‐9‐THC treatment (1 mg/kg/day s.c.). Before treatment, the following order of potency was obtained: CP 55940>JWH‐018> delta‐9‐THC=JWH‐073. After 3 days of delta‐9‐THC treatment, the potency of delta‐9‐THC and JWH‐018 to produce discriminative stimulus effect was decreased. ED50 values were increased for delta‐9‐THC 2.9‐fold and for JWH‐018 2.4‐fold. In contrast, delta‐9‐THC produced no significant decrease in the potency of CP 55940 and JWH‐073 to produce discriminative stimulus effects (p>0.05). Fourteen days of delta‐9‐THC treatment increased the ED50 value for delta‐9‐THC 7.2‐fold and for CP 55940 4.2‐fold. Taken together, the hypothesized relationship between efficacy and the magnitude of tolerance/cross‐tolerance was supported only for delta‐9‐THC and CP 55940. In contrast to in vitro data, these results suggest that JWH‐018 has relatively low and JWH‐073 relatively high CB1 receptor agonist efficacy in vivo.
Sensitivity to the rewarding and locomotor effects of amphetamine following early treatment with methotrexate and cytarabine in adolescent mice
Authors: Myers Alyssa M , Bisen-Hersh Emily B , Walker Ellen A
Published: June 2021

Stimulants such as amphetamine (AMPH) are popular medications for the cognitive late effects of childhood cancer treatment. While the reinforcing and stimulatory properties of AMPH are well documented, little is known about these effects in childhood cancer survivors. In this study, conditioned place preference (CPP) and locomotor activity were measured to investigate sensitivity to AMPH in adolescent (PND 35) mice following neonatal exposure to chemotherapeutic agents methotrexate (MTX) and cytarabine (Ara‐C). Mice were treated with saline, MTX (2.0 mg/kg), Ara‐C (20 mg/kg) or a combination of MTX and Ara‐C (2.0 mg/kg and+ 20 mg/kg) at PND 14, 15, and 16. At the low dose of AMPH (1 mg/kg), chemotherapy‐treated mice spent significantly more time on the AMPH‐paired side. MTX and Ara‐C treated mice showed higher activity levels compared to saline following each AMPH injection, but only the Ara‐C group displayed behavioral sensitization across repeated AMPH exposure. At the high dose of AMPH (4 mg/kg), only mice treated with Ara‐C spent significantly more time on the AMPH‐paired side. All groups showed a higher activity level following the first AMPH injection compared to baseline. Findings suggest that sensitivity to the rewarding and locomotor effects of AMPH is enhanced following early treatment with MTX and Ara‐C. Since these effects were observed at a lower AMPH dose compared to the saline‐treated group, it may be that the dose‐response curve for AMPH has shifted following early chemotherapeutic treatment. (Supported by CA129092 and T32 DA07237).
In vivo effects of “bath salt” constituent 3,4‐ methylenedioxypyrovalerone (MDPV) in mice: contribution of ambient temperature and monoamines
Authors: Fantegrossi William E. , Zimmerman Sarah M. , Rice Kenner C.
Published: June 2021

Designer stimulants are rapidly emerging as drugs of abuse. Marketed as “bath salts” or “plant food,” these commercial products typically contain cathinone analogues such as 3,4‐methylenedioxypyrovalerone (MDPV), but little is known about the underlying in vivo pharmacology of these drugs. In these studies, we assessed the effects of MDPV on core temperature and locomotor activity in mice as a function of ambient temperature. Further studies extended these findings by depleting serotonin (5‐ HT) or catecholamines (DA and NE) in order to gauge the role of these neurotransmitter systems in the in vivo effects of MDPV. Across a range of doses, MDPV elicited locomotor stimulant effects at 20°C, and increasing the ambient temperature to 29°C potentiated this action. Similarly, MDPV induced hyperthermic effects in mice at the cool ambient temperature, but hyperthermia was even more profound at 29°C, where lethality also occurred. Depletion of central 5‐HT did not alter the locomotor stimulant effects of MDPV, but exacerbated the hyperthermic effects of this compound, while depletion of catecholamines attenuated the locomotor stimulant effects of MDPV without altering the thermoregulatory effects of this drug. These findings suggest that ambient temperature is a critical factor in evaluating the in vivo pharmacology of MDPV, which seems to involve a mixture of serotonergic, dopaminergic, and perhaps noradrenergic systems in the mouse. In vivo studies were supported by US PHS Grant RR020146 and a Pilot Research Award from the University of Arkansas for Medical Sciences Center for Clinical and Translational Research (RR029884). The work of the Drug Design and Synthesis Section was supported by the NIH Intramural Research Programs of the NIDA and the NIAAA.