bluuebunny/crossref_metadata_2025 huggingface dataset:
Korean pine nut oil attenuated hepatic TG accumulation in high‐fat diet‐induced obese mice
Authors: Park Soyoung , Shin Sunhye , Lim Yeseo , Shin Jae Hoon , Seong Je Kyung , Han Sung Nim
Published: June 2021

Korean pine nut oil (PNO) has been reported to have some influence on weight gain and lipid metabolism. We examined whether PNO replacement in high‐fat diet (HFD) can ameliorate HFD‐induced hepatic steatosis compared to soybean oil (SBO). Five‐wk‐old C57BL mice were fed control diets containing 10% energy fat from PNO or SBO (PC, SC) or HFD with 45% energy fat from 10% PNO or SBO and 35% lard (PHFD, SHFD) for 12 wks. Mice in PHFD group gained less body weight (10% less, P = 0.02) and had less white adipose tissue (18% less, P = 0.03) compared to those in SHFD group without significant food intake reduction. Hepatic TG levels tended to be greater in mice fed HFD (P = 0.08) than those fed the control diets. PHFD group had significantly lower hepatic TG level than SHFD group (P = 0.001). Overall, PNO upregulated hepatic Acadl mRNA expression (P = 0.05). Expression of hepatic Pparg mRNA was downregulated in PC group compared to SC group (P = 0.003). Protein expression of SIRT3 in white adipose tissue was downregulated in SHFD group (P < 0.001) and was restored in PHFD group to the level of control lean mice (P = 0.003). In conclusion, PNO consumption resulted in less body fat accumulation and attenuated hepatic steatosis in HFD‐induced obesity, which seemed to be a result of caloric restriction‐mimetic response despite no significant change in food intake.

Supported by the grant from National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant no. 20110027052)
Atypical antipsychotics attenuate associations between linoleic acid and reduced markers of metabolic syndrome
Authors: Evans Simon J , Prossin Alan R , McInnis Melvin G , Burant Charles F , Ellingrod Vicki L
Published: June 2021

Atypical antipsychotic (AAP) use in psychiatric patients is associated with the development of metabolic syndrome, which includes increased waist circumference, dyslipidemia, and insulin resistance. Dietary or supplemental polyunsaturated fatty acids (PUFA) can have positive effects on these symptoms in the general population. Studies from our group suggest that AAP may reduce the beneficial effects of PUFA. We have previously reported a positive association between total omega‐3 dietary intake and endothelial function in schizophrenic subjects not taking AAP that was absent in subjects taking AAP. Here we report, in a population of 27 bipolar subjects, potential interactions between AAP use and serum concentrations of the omega‐6 PUFA, linoleic acid. Serum levels of linoleic acid negatively associated with markers of inflammation (TNF‐alpah); glycemic control (insulin, hemoglobin A1c (HbA1c), glucose); cardiovascular health (triglycerides, homocysteine); and obesity (BMI, waist‐to‐hip ratio). In several of these associations, regression analysis showed stronger correlations in subjects not taking AAP than in those taking the medications and statistical analysis confirmed an interaction between AAP and LA. These data suggest that AAP use may attenuate the health benefits of PUFA and pose the question whether increased PUFA intake can overcome the negative health effects of AAP.
Comparison of zinc protoporphyrin concentration in capillary whole blood and venous washed red blood cells among young Burkinabe children
Authors: Hess Sonja Y , Yakes Elizabeth , Abbeddou Souheila , Peerson Janet M , Some Jerome W , Ouedraogo Zinewende , Ouedraogo Jean‐Bosco , Brown Kenneth H
Published: June 2021

Background

Zinc protoporphyrin (ZPP) is a useful indicator of iron (Fe) status. Washing red blood cells (RBC) prior to ZPP analysis has been advised to avoid false positives in individuals with malaria, but this procedure adds complexity to sample processing.

Objective

To compare ZPP in capillary whole blood samples (ZPPcap) and washed RBCs from venous blood (ZPPven) among young Burkinabe children in a malaria endemic region.

Methods

Capillary and venous lithium‐heparinized blood samples were collected within 0–4 d in children aged 9 mo (n=592). The RBCs of venous samples were washed twice using saline solution. ZPPcap and ZPPven concentrations were assessed by hematofluorometer (AVIV). Malaria was identified using HRP‐II rapid diagnostic test, and presence of inflammation was based on C‐reactive protein (CRP ≥5 mg/L) and/or α‐1‐acid glycoprotein (AGP ≥1 g/L).

Results

The median (range) of ZPPcap and ZPPven were 212.3 (20.3–1526.7) and 136.5 (11.5–1455.5) μmol/mol heme, respectively. The mean ZPPcap is higher than the mean ZPPven (p<0.0001), but the log transformed ZPPcap and ZPPven concentrations are highly correlated even in the presence of malaria and inflammation (r=0.88–0.92; p<0.0001).

Conclusion

Unwashed whole blood can be used to determine Fe deficiency by ZPP, even in the presence of malaria or inflammation.

Funded by the Bill & Melinda Gates Foundation.
Phospholipid PUFA: a better indicator for assessing health risks
Authors: Li Yong , Friedman Allon A , Yu Zhangsheng , Tamez Hector , Wenger Julia , Thadhani Ravi , Watkins Bruce A
Published: June 2021

Long chain (LC) PUFA are major components of cell membrane phospholipids (PL) serving as precursors for bioactive lipid derivatives. Fatty acids (FA) are routinely analyzed in biological samples to assess its composition. In human studies, serum or plasma is often used because of their easy procurement. The blood lipid pool is a mixture of triglycerides (TG), PL, cholesterol and its esters, and other components. Here, we report findings in serum FA analysis after fractionation of polar and neutral lipids by SPE. LC PUFA were found concentrated in the polar fraction compared to neutral and total lipid fractions. When correlated with clinical data, e.g., systolic BP and cholesterol, a greater number of significant correlations were found for FA in polar compared to total or neutral fractions. We showed that the polar lipid is a more stable reflection of LC PUFA status compared to the other fractions because the latter are diluted by non‐essential FA. The relative amounts of LC PUFA in total and neutral fractions reflect the contribution of TG in blood that varies with age and physiologic state. Our data indicate that LC PUFA in the polar faction are superior indicators of health status and disease risk that could be applied in establishing meaningful links between PUFA status and biomarkers of disease and health outcomes. (Supported by NIH fund DK084403 & the National Kidney Foundation)
Metabolic Effects of Bedtime Pistachio Consumption for 6 weeks in Overweight Persons
Authors: Anderson Ashley Dawne , Anderson Melanie M , Jacobson Janel L , Popko Mackenzie R , Young Jessica R , Limburg Paul J , Wilson Ted
Published: June 2021

Mono‐and polyunsaturated fats in nuts, such as pistachios (PI), may improve lipoprotein and glycemic status. Overweight persons trend for dyslipidemia and high diabetes risk. The lower limits of PI consumption required for health benefits are unknown. This study determined if PI at bedtime promotes beneficial changes in metabolic status in overweight persons. Overweight subjects (n=22; 55 ± 2 yrs; 90 ± 3.6 kg; BMI 31 ± 1) were randomized to 35.4 g PI self‐administered at bedtime or control (CO; no PI) for 6 weeks. There was no difference in physical activity level between subjects receiving PI and CO. Body weight was not different in PI and CO at wk 0, 1, 2, 4, and 6. HDL cholesterol at wk 0 and 6 in PI was 49.2 ± 3.5 to 50.3 ± 3.0, and CO was 60.8 ± 3.8 and 58.0 ± 2.7 mg/dL, at wk 6 PI had improved slightly relative to CO (P= 0.12). Plasma glucose at wk 0 and 6 in PI was 104.6 ± 2.8 and 99.6 ± 2.6 mg/dL, and CO was 102.0 ± 2.8 and 101.1 ± 2.6 mg/dL, at wk 6 PI had improved slightly relative to CO (P= 0.16). Plasma insulin at wk 0 and 6 in PI was 8.5 ± 1.0 and 8.4 ± 0.9, and CO was 7.2 ± 0.7 to 8.8 ± 0.7 μU/mL, at wk 6 PI had improved slightly relative to CO (P = 0.21). Beneficial changes in HDL, glucose, and insulin probably requires slightly more than 35.4 g/d PI for 6 wks. To increase the probability of metabolic health benefits, nutritionists may wish to encourage levels of daily PI consumption higher than those administered in this study.
Calorie intake and blood lipidomics
Authors: Kristal Bruce , Hubbard Van S , Starke‐Reed Pamela , Bird Susan S , Marur Vasant R , Sniatynski Matt , Sheldon Diane
Published: June 2021

Weight loss is inherently linked to the utilization of stored fats and should be detectable as changes in the blood lipidome. Such lipid changes may serve as biomarkers and may reveal protective responses, eg, in markers associated with insulin resistance or risk of type II diabetes. Conversely, fat utilization may be biased, at least initially, towards the metabolism of unsaturated fats vs saturated fats, which could have important public health consequences, as acute weight‐loss might be a period of exposure conditions that favor atherosclerosis development.

Testing these issues in FBNF1 rat models of both stable and acute weight loss/caloric restriction (CR) enabled control of diet quantity/quality and minimized confounds. Rats were fed ad libitum, different periods of 40% CR (1, 2, 4, 8, or 18 weeks), or 10–40% CR for 8 weeks. Sera lipids were assessed using a high resolution mass spectrometry‐based analysis that detected >;500 intact lipids (>;300 structurally identified), spanning 6 LIPIDMAPS categories. Data supporting both issues above were observed. Data are also compared with metabolomics biomarkers for: (i) CR defined in rats that cross‐species to reflect caloric intake and future disease risk in humans, and; (ii) relative intakes and quality of dietary protein, carbohydrate, and fat. Complementary analyses are in progress in the NIA CALERIE trial of CR in humans. NIH support
Current intake of animal and vegetable protein in the US: What We Eat In America (WWEIA)/National Health and Nutrition Examination Survey (NHANES), 2007–2010
Authors: Fulgoni Victor L , Keast Debra R , O'Neil Carol E , Nicklas Theresa A
Published: June 2021

The animal protein and vegetable protein content of foods consumed in WWEIA/NHANES 2007–2010 were calculated using the relevant USDA Nutrient Database for Standard Reference (SR), the SR‐Link recipe file of the respective Food and Nutrient Database for Dietary Studies, and the MyPyramid Equivalent Database. Animal protein and vegetable protein intake were determined by age/gender groups with and without energy adjustment. In subjects 2+ yrs (N=17,387), animal protein intake was 53.0 ± 0.5 g/d while vegetable protein intake was 25.8 ± 0.2 g/d. Females (2+ yrs) had lower animal protein intake than males even after adjusting for energy intake (50.4 ± 0.5 v 55.7 ± 0.5 g/d; p<0.01). Similar gender differences were seen for all age groups evaluated except those 2–8 yrs (38.6 ± 0.6 v 39.8 ± 0.9 g/d in males and females, respectively; NS). Older adults (>;70 yrs) had lower animal protein intakes as compared to younger adults (19–30 yrs) even after adjusting for energy intake in males (43.0 ± 0.9 v 61.9 ± 1.3 g/d; p<0.01) and females (40.3 ± 0.6 v 55.5 ± 1.1g/d; p<0.01). The ratio of animal to vegetable protein was remarkably similar across age/gender groups, ranging from 1.8–2.2. In summary, animal protein was the predominant protein consumed, especially by males, and more studies are needed to better understand how demographic differences described influence the nutrient profiles of the diet. Support: USDA and The Beef Checkoff.
Plant and animal protein intakes are differently associated with nutrient adequacy in French adults
Authors: Verger Eric Olivier , Camilleri Géraldine M , Huneau Jean‐François , Carpentier Florence , Dubuisson Carine , Mariotti François
Published: June 2021

The objective was to study the relations between animal and plant protein intake and the diet quality, as captured by an integrated index of nutrient adequacy. Using data from the French national dietary survey, INCA2 (2006–2007) for 1912 adults, we assessed diet quality with the PANDiet, based on the 35 probabilities of having adequate nutrient intakes. We used multiple regression analysis to study the relation with the intakes of plant, animal, and related food sources proteins. Plant protein intake was positively associated with the PANDiet, irrespective of gender (β=0.50; P<0.0001). In contrast, animal protein intakes were differently associated with the PANDiet, positively in women (β=0.08; P<0.0001) and negatively in men (β=−0.05; P<0.005). Relations between the PANDiet and intakes of animal food proteins were varied. Red meat and poultry protein intakes were negatively associated with the PANDiet in men but not in women. Furthermore, irrespective of gender, we found positive associations for fish, milk and yoghurt protein intakes and negative associations for eggs, offal, processed meat and cheese protein intakes. These findings show that plant protein is a robust marker of a high‐quality diet, whereas total animal protein hides different subtypes of animal food protein that display very contrasted relations with diet quality. These data could help to refine proteins recommendations.
Relationship between leukocyte global DNA methylation and RBC folate in the Women's Health Initiative Observational Study (WHI‐OS)
Authors: Bae Sajin , Caudill Marie A , Bailey Lynn B , Malysheva Olga , Miller Joshua W , Brown Elissa C , Neuhouser Marian L , Maneval David , Cheng Ting‐Yuan David , Hou Lifang , Beresford Shirley A A , Song Xiaoling , Zheng Yingye , Buck Katharina , Ulrich Cornelia M
Published: June 2021

This study investigated the impact of folic acid (FA) fortification on global DNA methylation and its relationship with RBC folate in the WHI‐OS. We selected ~400 postmenopausal women (50–79 y) from the highest (891 ± 210 ng/mL, mean ± SD; n=206) and lowest (350 ± 79 ng/mL; n=202) tertiles of RBC folate distribution matching on age and time of blood draw: pre, peri, or post‐FA fortification. Global DNA methylation was measured in blood leukocytes collected at study baseline using liquid chromatography‐mass spectrometry. No differences (P=0.86) in DNA methylation were detected between the pre (5.04 ± 0.4%), peri (5.05 ± 0.4%), or post (5.03 ± 0.4%) FA periods (1‐way ANOVA). However, methylation was lower (4.9 vs. 5.2%; P =0.01) in the highest (859 ± 188 ng/mL, n=53) vs. the lowest (371 ± 88 ng/mL, n=29) RBC folate tertile in the post‐FA period (t‐test). Additional analyses are underway to explore possible interactions between FA fortification and RBC folate on global DNA methylation among postmenopausal women.

Funded by NIH R01 CA120523, N01WH22110, HHSN26820110
Effects of polyphenolic‐rich dark chocolate/cocoa and almonds on established and emerging cardiovascular risk factors: study design
Authors: Berryman Claire E , West Sheila G , Chen C‐Y Oliver , Blumberg Jeffrey B , Fleming Jennifer A , Preston Amy G , Miller Debra L , Kris‐Etherton Penny M
Published: June 2021

Almonds are recognized for their cholesterol‐lowering effects and polyphenolic‐rich dark chocolate/cocoa for blood pressure and vascular health benefits. This research seeks to evaluate the individual, additive, and synergistic effects of almonds and/or dark chocolate/cocoa on CVD risk. A randomized, 4‐period, crossover controlled feeding study was designed to compare the effects of a healthy American diet (49% CHO, 17% PRO, 34% FAT, 13% SFA, 276 mg/d CHOL, no almonds, dark chocolate, or cocoa/d) to three diets incorporating almonds (49% CHO, 16% PRO, 35% FAT, 8% SFA, 153 mg/d CHOL, 1.5 oz. almonds/d, no dark chocolate or cocoa/d), dark chocolate/cocoa (53% CHO, 16% PRO, 32% FAT, 11% SFA, 157 mg/d CHOL, no almonds/d, 43g dark chocolate/d, 11g natural cocoa/d), or both (50% CHO, 16% PRO, 34% FAT, 8% SFA, 116 mg/d CHOL, 1.5 oz. almonds/d, 43g dark chocolate/d, 11g natural cocoa/d). The study population will be 40 men and women (BMI 26–35 m/kg2) with LDL‐C in the 25–95th percentile. We hypothesize that the almond, dark chocolate/cocoa, and almond + dark chocolate/cocoa diets will improve CVD risk factors compared to the control diet; however, the greatest improvements will be observed with the almond + dark chocolate/cocoa diet on the basis of lipids/lipoproteins, blood pressure, vascular function, inflammatory response, and (anti)oxidant status.

Grant Funding Source: Almond Board of California and Hershey Center for Health & Nutrition
Effects of Walnuts on Vascular Function and Platelet Reactivity in Postmenopausal Women with Hypercholesterolemia
Authors: Yim Sun Jung , Djurica Dragana , Holt Roberta R , Keen Carl L , Hackman Robert M
Published: June 2021

Walnuts contain a number of phenolic acids, polyphenols and lipids that may benefit cardiovascular health. We examined the effects of acute (4 hours) and short‐term (4 weeks) walnut intake on select cardiovascular outcome measures. Thirty‐six hypercholesterolemic postmenopausal women were randomly assigned to consume 5 or 40 g of walnuts daily for 4 weeks in a parallel‐arm design. Outcomes were measured after an overnight fast, and 4 hours after walnut intake on the first day of the study (V1) and after 4 weeks (V2) and included microvascular function as assessed by peripheral arterial tonometry (PAT), platelet function (PFA‐100), and serum lipids. Data are presented as mean ± SD. No significant changes in PAT were noted after 5 g of walnut intake. However, 40 g of walnut intake for 4 weeks was associated with an increased PAT response after an overnight fast (V1: 2.32 ± 0.39 vs. V2: 2.70 ± 0.31; p=0.008). An increase in PAT was also observed 4 hours after 40 g of walnut intake on V1 (2.32 ± 0.39 vs. 2.82 ± 0.39; p=0.001), but not on V2. LDL concentrations were decreased 4 weeks after 40 g/day of walnut intake (V1: 154.76 ± 16.79 mg/dL vs. V2: 146.06 ± 17.33 mg/dL). No significant changes were found in platelet function or other lipids in either group. The results suggest that the chronic consumption of 40 g of walnuts can result in positive vascular effects. This work was supported by the California Walnut Commission.

Grant Funding Source: The California Walnut Commission
Anti obesity effect of GTF extracts in high fat diet‐induced obesity mice
Authors: Park Soojeung , Kim Ok‐Kyung , Nam Da‐Eun , Ho Jin‐Nyung , Yoo Seon‐A , Han Dong‐kyu , Kwon Han‐ol , Lee Jeongmin
Published: June 2021

Green tea is one of the most popular beverage and it have been studied for the prevention of obesity. The aim of this study was to investigate whether a Green tea fruit extracts (GTFE) such as Hot water (HW), 95% EtOH (E), Defatted supercritical fluid (DSF) and Concentrated supercritical fluid (CSF) have an effect on weight loss in high fat diet‐induced obesity mice. Each of GTFE was fed with a high fat diet (60% kcal% fat) to C57BL/6J mice at 200, 500mg/kg/day for 13 weeks. After the experiment period, weight gain, viscerals weight, the size and number of adipocyte, serum and hepatic lipid profile were measured. We found that GTFE diet effectively decreased body weight, liver weight, the size and number of adipocyte, serum triglyceride and total cholesterol levels, hepatic triglyceride and total cholesterol levels (p<0.05) in order of DSF 500 >; DSF 200 >; E 500 >; E 200 >; CSF 500 >; CSF 200 >; HW 500 >; HW 200 mg/kg/day compared to control group. Also, GTFE diet effectivly increased serum HDL‐cholesterol and glycerol levels (p<0.05) in order of DSF 500 >; DSF 200 >; E 500 >; E 200 >; CSF 500 >; CSF 200 >; HW 500 >; HW 200 mg/kg/day compared to control group. These results suggest that GTFE is useful in the chemoprevention or treatment of obesity.
Effects of Dietary Protein and Vitamin A on Retinoids and Retinol binding Protein in Periparturient rats
Authors: Foroudi Farhad , Ramsey Kirk C. , Rezamand Pedram
Published: June 2021

Our objective was to study the effect of dietary vitamin A and protein on retinoid metabolism and retinoid binding protein (RBP) in vivo. Before the initiation of treatments (confirmed pregnancy), 4 rats were euthanized with blood and tissue samples obtained to establish baseline measures. Female rats, ~21 d before parturition, were fed rations altered in protein (13 or 22%) and vitamin A contents (3 or 5 IU/g). Samples were collected at d −14 (before parturition), d +3, and +10 postpartum via cardiac puncture under anesthesia (n=3–4/ group). Serum RBP showed no significant differences among treatments. Serum and liver 13‐cis retinoic acid (13‐cis), all‐trans retinoic acid (all‐trans) and retinol contents showed no differences, whereas serum all‐trans and retinol concentrations differed at −14 and +3 relative to baseline. The liver 13‐cis and all‐trans were significantly altered on d +3 and +10, and on d −14 relative to baseline, respectively. Treatments and time affected small intestine content of 13‐cis on d −14 and +3, and on d −14 and +10, respectively. The liver mRNA expression of RBP tended to differ for High Protein‐ High Vitamin group than other groups on d −14, whereas the liver TNF‐α gene expression tended to be lower for High Protein‐Low Vitamin group than other groups on d +3. Physiological state and dietary treatments affected the status of retinoids and RBP differently around the time of parturition.
Amiloride Derivative Phenamil Restricts Long Bone Growth in Broilers in Conjunction with Zinc Accumulation
Authors: Price Tara , Moncada Kristin L , Park Kye Won , Tontonoz Peter , Walzem Rosemary L.
Published: June 2021

Phenamil induces osteoblast formation and calcification in murine mesenchymal cultures. In vivo bioactivity in broiler chicks was studied during rapid bone growth 2 weeks post hatch. 26 broiler chicks were intubated daily with DMSO Vehicle (V) or 30 mg Phenamil (P)/kg BW. Body weight was measured to day 15 in ad lib fed birds. Tibia & femur fresh (f) and dry (d) weight, length, mid‐shaft width, % ash and mineral composition were measured. P‐birds weighed less than CON on days 8 through 14 (p< 0.03), but not at day 15 (p< 0.28). Tibiaf and femurf weights from P‐birds were less than CON (p< 0.005, p< 0.002), but only tibiad weight as %BW differed (p< 0.04). Femurd weights did not differ. Tibiasd from P‐birds weighed less than CON (p< 0.011), but not as a %BW. Bone ash as % of BW did not differ.

Tibiasf from P birds were shorter (p<0.004) & more narrow (p< 0.012) than CON. Femur lengths and widths were similar as was dry bone, bone ash %. Bone ppm of P, K, Ca, Mg, Na, Fe, Cu, Mn, S, and B were similar, while bone Zn increased 30% in P‐birds (p< 0.001) along with a 2.6% increase in bone Ca:P (p< 0.003). Phenamil restricted long bone growth of young broilers while enhancing relative bone Ca and absolute bone Zn deposition. Phenamil effects on normal bone growth as compared to bone repair need additional study. Supported in part by Undergraduate Research funds to KM. Animal Protocol #2012–028 IAUCC‐TAMU
Association of HER2 Ile655Val and Ala1170Pro polymorphisms with breast cancer prognosis factors
Authors: Furrer Daniela , Laflamme Christian , Côté Marc‐André , Provencher Louise , Barabé Frédéric , Jacob Simon , St‐Pierre Christine , Demers Éric , Tremblay‐LeMay Rosemarie , Nadeau‐Larochelle Corinne , Michaud Annick , Lemieux Julie , Diorio Caroline
Published: June 2021

The human epidermal growth factor receptor‐2 (HER2) overexpression occurs in about 15% of human breast cancers and is a marker of poor survival. However, it is unclear if common HER2 polymorphisms are associated with breast cancer prognosis factors. This study aimed to evaluate the association between HER2 polymorphisms and breast cancer prognostic factors in non‐metastatic HER2‐positive breast cancer patients. Among 73 women, HER2 polymorphisms (Ile655Val and Ala1170Pro) were assessed using TaqMan assays in normal and tumor breast tissues. In normal breast tissue, the variant allele 1170Pro was associated with younger age (P=0.007) and the presence of lymphovascular invasion (P=0.06). Similar associations were observed when polymorphism was assessed in tumor breast tissue. No association was found between Ile655Val polymorphism and breast cancer prognostic factors. However, we observed a difference of Ile655Val or Ala1170Pro genotyping between normal and tumor breast tissues (P=0.03 and P=0.01, respectively). These preliminary results suggest that HER2 Ile655Val and Ala1170Pro polymorphisms may play a role in breast carcinogenesis, but only Ala1170Pro polymorphism is associated with breast cancer prognostic factors in non‐metastatic HER2‐positive breast cancer patients.
Activation of pattern recognition receptors in brown adipocytes induce proinflammatory genes and suppress uncoupling protein 1 mRNA expression
Authors: Bae Jiyoung , Ricciardi Carolyn J , Chen Jiangang , Zhao Ling
Published: June 2021

Brown adipose tissue (BAT) plays a critical role in nonshivering thermogenesis and energy disposal in contrast to white adipose tissue (WAT), which is responsible for energy storage. Recent evidence shows that two families of pattern recognition receptors (PRR), Toll‐like receptors (TLR) and Nucleotide‐oligomerization domain containing proteins (NOD), play critical roles in inflammation in white adipocytes and WAT. However, the role of TLR and NOD in brown adipocytes and BAT remains to be determined. Here, we report that mRNA of TLR4, TLR2, NOD1 and NOD2 is increased in BAT of diet‐induced obese mice, genetically obese ob/ob mice, and differentiated brown adipocytes compared to undifferentiated cells. Moreover, stimulation of TLR4, TLR2 and NOD1 with their respective synthetic ligand induce mRNA expression of proinflammatory chemokine/cytokine MCP‐1, RANTES, IL‐6 and TNF‐α and suppress mRNA expression of uncoupling protein‐1 through modulation of MAPK‐dependent and/or NF‐κB‐responsive pathways in brown adipocytes. Together, our results suggest that PRRs may play important roles in inducing inflammation and dysfunction in BAT in obesity. The work is supported by The University of Tennessee faculty start‐up funds to L.Z.
Mechanism of glabridin‐mediated vasorelaxation of rat main mesenteric artery
Authors: Aaronson Philip , Chanda Debrabata
Published: June 2021

Glabridin is one of the major flavonoids found in Glycyrrhiza glabra (licorice) root, an important traditional Chinese medicine, and has been reported to have anti‐atherogenic, anti‐inflammatory and anti‐nephritic properties. Because its acute effect on vascular tone remains unknown, we examined whether glabridin was able to relax rat main mesenteric arteries (RMMA) which had been preconstricted with norepinephrine or U46619. RMMA were mounted on a Mulvany‐Halpern type myograph and isometric tension development was monitored. Glabridin caused a relaxation of preconstricted RMMA at a concentration of as little as 0.1 μM, with a relaxation of ~70% being recorded at a concentration of 30 μM. Relaxation was endothelium‐independent, and was strongly inhibited if the K+ concentration in the bathing solution was raised to 20 mM. Relaxation was also strongly antagonized by inhibiting BKCa channels (with 1 mM TEA), KV channels (with 300 μM 4‐AP), or KATP channels (with 10 μM glibenclamide). These results indicate that glabridin, in a concentration range relevant to that which it may attain in plasma in vivo, induces a vasorelaxation which requires vascular smooth muscle hyperpolarization, possibly mediated by the opening of several types of K+ channels.
Behavioral effects of quinpirole on schedule‐controlled responding in radiation sensitive and insensitive rats
Authors: Davis Catherine Marie , Hienz Robert D.
Published: June 2021

A previous report noted that rats receiving head‐only exposure to iron ions (56Fe, a form of ionizing radiation) displayed neurobehavioral deficits on the rodent psychomotor vigilance task (rPVT), including changes in accuracy and premature responding, that were only apparent in a subset of exposed rats; i.e., radiation‐sensitive and insensitive groups emerged. Group‐specific changes in dopamine (DA) protein levels were also evident.

To better understand DA system differences in radiation sensitivity, these radiation‐sensitive and insensitive groups and a sham‐irradiated control group were subsequently trained to press a lever for food pellets on a fixed‐ratio 30 schedule of reinforcement. The D2 receptor agonist quinpirole (0.01–1.0 mg/kg) dose‐dependently decreased response rates in all groups; irradiated groups were more sensitive than controls (i.e., showed greater decreases). The D2 receptor antagonist amisulpride (0.1–2.0 mg/kg) alone had no effect on performance, but did antagonize quinpirole's effects. The results show that the DA system is sensitive to radiation‐induced changes that alter behavior as exemplified by the DA system's response to drug administration, which could impact treatment of radiation‐induced cognitive deficits. This work was funded by NSBRI through NASA NCC 9–58‐PF02602 and 9–58‐NBPF02802.
Loss of sensitivity to varenicline in monkeys receiving chronic nicotine treatment.
Authors: Cunningham Colin Seamus , McMahon Lance Richard
Published: June 2021

Given the adverse health consequences of tobacco use, there is a need to understand pharmacologic mechanisms of drug action as a function of nicotine treatment. Here, the effects of nicotine and varenicline (Chantix) were compared under two distinct conditions of nicotine treatment. One group (n=5) of rhesus monkeys discriminated nicotine base (1.78 mg/kg) from saline; the same dose of nicotine was discriminated by a second group of monkeys that received 8.9–10.68 mg/kg/day. Nicotine dose‐dependently increased nicotine‐lever responding in both groups; the ED50 value without daily nicotine treatment (0.47 mg/kg) was not different from that with daily nicotine treatment (0.30 mg/kg). In contrast, varenicline produced 98% nicotine‐lever responding in monkeys not receiving nicotine daily (ED50 value = 0.53 mg/kg), but only produced a maximum of 10% nicotine‐lever responding in monkeys receiving nicotine daily. Although a loss in the discrimination of varenicline in monkeys receiving large doses of nicotine daily is consistent with varenicline having lower agonist efficacy than nicotine, their combined effects did not confirm this possibility inasmuch as varenicline did not shift the nicotine dose‐effect function rightward. A difference in agonist efficacy at a common receptor type is not sufficient to account for the striking loss of sensitivity to varenicline resulting from nicotine treatment.
Induction of cytochrome P450 (CYP) 2E1 expression by placental lactogen.
Authors: Lee Jin Kyung , Chung Hye Jin , Pan Xian , Ingelman‐Sundberg Magnus , Jeong Hyunyoung
Published: June 2021

Pregnancy alters hepatic drug metabolism, but the underlying mechanism remains to be identified. In this study, we evaluated the effects of pregnancy‐specific somatotropins [placental lactogen (PL), prolactin (PRL), and growth hormone variant (GH‐v)] on expression of major hepatic CYPs. In human hepatocytes, PL significantly increased the expression of mRNA and protein of CYP2E1 (2.8–5.1 fold), leading to 74% increases in chlorzoxazone 6‐hydroxylation activity. In contrast, PRL and GH‐v had insignificant effects on CYP expression. Considering that somatotropins share common downstream signaling pathways, transcription factors that uniquely modulate PL action were identified by (1) microarray analysis of human hepatocytes treated with vehicle, PL, or PRL, (2) followed by in silico promoter analysis. The results revealed that responsive elements for 7 classes of transcription factor (CREB, ETS factor, class B bHLH transcription factors, homeodomain transcription factors, paralog hox genes, Krüppel like factors, and STAT) exist in promoters of 60% of 125 PL‐responsive genes. PL increased CYP2E1 promoter activity in STAT5‐expressing HepG2 cells. Collectively, our findings indicate that PL increased CYP2E1 expression, in part through STAT5; CYP2E1‐mediated drug metabolism may be increased during pregnancy, resulting in differential drug efficacy and/or toxicity in pregnant women. (HD065532)
The role of cytochrome P450‐dependent metabolism in the regulation of mouse hepatic growth hormone signaling components and target genes by 3‐methylcholanthrene
Authors: Riddick David S , Lee Chunja , Ding Xinxin
Published: June 2021

State Department of Health, Albany, NY 3‐Methylcholanthrene (MC), a readily metabolized aryl hydrocarbon receptor (AHR) agonist, disrupts mouse hepatic growth hormone (GH) signaling and suppresses cytochrome P450 2D9 (Cyp2d9), a male‐specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). To determine if these effects depend on hepatic microsomal P450‐mediated activity, we examined MC responses in LCN mice with hepatocyte‐specific deletion of NADPH‐cytochrome P450 oxidoreductase (POR). MC caused mild induction of Por and a hepatic inflammatory marker in wild‐type mice whereas strong induction by MC of AHR target genes, Cyp1a1, Cyp1a2, and Cyp1b1, occurred in wild‐type and LCN mice. Two STAT5b target genes, Cyp2d9 and major urinary protein 2 (Mup2), were suppressed by MC in wild‐type mice and the CYP2D9 mRNA response was maintained in LCN mice. In wild‐type mice, MC decreased GH receptor (GHR) mRNA but increased GHR protein levels. There was a trend for impairment of STAT5 phosphorylation by MC in both mouse strains. Basal levels of MUP2 mRNA, GHR mRNA and protein, and the activation status of extracellular signal‐regulated kinase 2 and Akt were influenced by hepatic Por genetic status. The effects of MC on hepatic GH signaling components and target genes are complex, involving aspects that are both dependent and independent of hepatic microsomal P450‐mediated activity. [Support: CIHR, NIH‐NCI]
Follistatin‐like 1 enhances cigarette smoke‐induced interleukin‐8 secretion from human airway smooth muscle cells.
Authors: Cernecka Hana , Poppinga Wilfred J , Jansen Sepp R , Schmidt Martina , van Den Hoff Maurice JB , Maarsingh Harm
Published: June 2021

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease mainly caused by cigarette smoke. The inflammation is importantly driven by infiltration and activation of neutrophils. Follistatin‐like 1 (Fstl1) is a TGF‐β inducible protein that acts as an inhibitor of bone morphogenetic proteins. Fstl1 induces the production of inflammatory cytokines, including the neutrophil attractant IL‐8. However, the role of Fstl1 in airway inflammation in COPD is currently unknown. Therefore, we studied the role of Fstl1 in cigarette smoke‐induced IL‐8 release from human airway smooth muscle (hASM) cells. Immortalized hASM cells were transfected with Fstl1 or GFP (control) and treated with or without cigarette smoke extract (CSE; 15%; 24h). Fstl1 mRNA expression was 12‐fold increased in the transfected cells. CSE also induced Fstl1 mRNA and protein in hASM cells by 1.5 fold. Transfection with Fstl1 did not affect basal IL‐8 release. However, CSE increased IL‐8 release by 2.2‐fold in control cells and this was potentiated 1.6‐fold after transfection with Fstl1. In conclusion, Fstl1 is increased by CSE and potentiates CSE‐induced airway inflammation. (NAF grant 3.2.12.083)
BXD mouse lines as a genetic reference population for metabolic syndrome
Authors: LAMY Sebastien
Published: June 2021

Chronic multifactorial diseases as type 2 diabetes and obesity result from interaction of genes and environmental factors. In order to better understand this interaction, a mouse genetic reference population allowing control of both conditions was used in a pipeline of standardized metabolic tests (such as exercise endurance, adaptive thermogenesis, glucose tolerance test) in a diet‐induced obesity paradigm with chow diet (CD) groups versus high‐fat diet (HFD) groups over 29 weeks. A panel of 42 BXD recombinant inbred mouse lines, descending from C57BL/6J and DBA2/J strains, was used to identify quantitative trait loci (QTL) and gene networks that modulate metabolic activity.

HFD groups showed a higher range in body weight increase than CD groups and significant differences in the BW loss after two weeks of voluntary exercise. Similarly, heterogeneity in the VO2 max, the cold resistance and the glucose tolerance is observed between strains and groups. After completion, the broad data set generated will enable QTL mapping strategies through the GeneNetwork resource.

The outcome of this work will provide a better understanding of the metabolic syndrome with the identification of signaling pathways and network regulations and will initiate new strategies for diagnosis, prevention and therapy complex diseases associated with aging.
Maternal‐fetal vitamin D status and child bone health
Authors: Huh Susanna Y , Aspinwall Sarah B , Rifas‐Shiman Sheryl L , Camargo Carlos A , Gordon Catherine M , Litonjua Augusto A , Gillman Matthew W
Published: June 2021

Objective

To examine whether maternal‐fetal vitamin D status is associated with child bone health.

Methods

In a prospective U.S. pre‐birth cohort, we studied 724 mother‐child pairs with 2nd trimester or cord 25(OH)D levels and dual‐energy X‐ray absorptiometry skeletal measures at 6.6–10.6 years.

Results

Mean (SD) 2nd trimester and cord blood 25(OH)D levels were 59 (22) and 45 (18) nmol/L, respectively. 25(OH)D levels were <50 nmol/L in 33% of 2nd trimester and 61% of cord blood samples. After covariate adjustment, neither 2nd trimester nor cord blood 25(OH)D were associated with total body bone mineral content (BMC) or areal bone mineral density (aBMD) (Table).

Conclusions

2nd trimester and cord blood 25(OH)D levels were not associated with child bone health.

Funded by NIH R01 grants HL064925, HD034568
Acute podocyte injury enhances the susceptibility to blood pressure‐induced injury in rats with underlying ¾ renal mass reduction
Authors: Polichnowski Aaron James , Picken Maria M. , Griffin Karen A. , Bidani Anil K.
Published: June 2021

The mechanism by which acute podocyte loss promotes chronic kidney disease (CKD) progression remains poorly understood. We administered a single dose (75 mg/kg i.p.) of puromycin aminonucleoside (PAN, n=14) or saline (sham, n=12) to male Sprague‐Dawley rats 2 weeks after ¾ renal mass reduction via surgical excision. BP was measured continuously every 10 minutes via radiotelemetry (DSI) and 24 hour urine protein excretion was determined weekly for 4 weeks following PAN administration. Two weeks after renal mass reduction and prior to administration of PAN the average systolic BP (125±3 vs. 129±3 mmHg) and 24‐hour proteinuria (8±1 vs. 18±7 mg/day) were similar in the PAN and sham groups, respectively. By contrast, four weeks after PAN administration the average systolic BP (147±4 vs. 135±5 mmHg; p<0.05) and 24 hour proteinuria (255±16 vs 34+8 mg/day; p<0.05) were significantly increased in the PAN vs. sham rats; respectively. Consistent with these findings, glomerulosclerosis (GS, 68±6% vs. 8+3% per 100 glomeruli; p<0.05) and the slope of the relationship between the %GS and average systolic BP (y=1.1x‐87 vs. y=0.4x‐52 %GS/mmHg) was also greater in PAN vs. sham rats; respectively. These data indicate that podocyte loss in the presence of impaired preglomerular autoregulation results in enhanced glomerular susceptibility to hypertensive injury with even modest increases in BP.
Dialysis Efficacy at Rest and During Intra‐dialytic Exercise: Agreement between Serum and On‐line Kt/V
Authors: Getz Carly , Parsons Trisha , Morton Ross , Toffelmire Edwin , King‐VanVlack Cheryl
Published: June 2021

The agreement between serum Kt/V values and on‐line Kt/V values was examined at rest and during intra‐dialytic exercise (IDE). On the middle dialysis session of the week, participants (n=10) underwent dialysis as usual for 2 weeks and cycled for 45–60 min during dialysis for another 2 weeks. Serum urea concentrations were measured pre‐ and post‐dialysis for calculation of Kt/V using the Jindal (JKt/V) and the Daugirdas (DKt/V) second generation equations. The On‐line Kt/V (OKt/V) value was recorded at the end of dialysis (Fresenius 2008K). All dialysate effluent was collected and the total urea (mmol) eliminated during each session was determined. No significant differences in Kt/V and total urea clearance values were found between rest and IDE. Excellent correlations were found between the JKt/V and DKt/V values at rest and during IDE (r=0.97). Very good associations occurred between OKt/V and the JKt/V and DKt/V values at rest and during IDE (r=0.83–0.86). Bland Altman analysis indicated a significant negative bias between the JKt/V value with respect to both the DKt/V (−0.128) and OKt/V (−0.163) values at rest and during IDE (−0.097, −0.203); as well as between the DKt/V and OKt/V values (−0.106) during IDE. The On‐line Kt/V provides the most conservative estimation of dialysis efficacy and potentially may be the best referral value from which to ensure achievement of minimally acceptable urea clearance.
Urea permeabilities in defined segments of rat renal inner medullary thin limbs of Henle's loops
Authors: Evans Kristen K , Pannabecker Thomas L , Dantzler William H
Published: June 2021

Urea permeabilities and resulting urea fluxes in specific segments of thin limbs of Henle's loops are critical to concentrating urine in rat renal inner medulla (IM) but have not yet been well‐defined. Immunohistochemistry has shown that urea transporter UT‐A2 is expressed in rat descending thin limbs (DTLs) near outer medullary (OM)‐IM border but not more than 0.5 mm below that point. No other urea transporters have been identified in rat IM. To understand the role that urea fluxes may play in the urine concentrating mechanism, we determined urea permeabilities (Purea) from 14C‐urea fluxes in perfused rat DTLs and ascending thin limbs (ATLs) isolated from 1) initial 2.5 mm below OM‐IM border (upper IM) and 2) terminal 2.5 mm of the IM (lower IM). Regardless of flux direction, Purea (x 10−5 cm/s) in upper IM was 49.6 ± 7.7 (mean ± SE) in DTLs and 192.9 ± 23.6 in ATLs. In lower IM, it was 208 ± 31 in DTLs and 225 ± 38 in ATLs. Phloretin (0.25 mM) had no effect on Purea in upper DTLs, suggesting that Purea was not due to the UT‐A2 transporter. Purea is similar (~200 × 10−5 cm/s) in lower DTLs and upper and lower ATLs, all segments that lack water channel AQP1 and have no osmotic water permeability, but is significantly lower (~50 × 10−5 cm/s) in upper DTLs, segments that express AQP1 and have high osmotic water permeabilities. Pathways or transporters accounting for urea permeabilities are unknown.
TRANSGENIC MICE EXPRESSING UT‐A1, BUT LACKING UT‐A3, HAVE INTACT URINE CONCENTRATING ABILITY
Authors: Klein Janet D. , Fröhlich Otto , Mistry Abinash C. , Kent Kimilia J. , Martin Christopher F. , Sands Jeff M.
Published: June 2021

Mice lacking the inner medullary collecting duct (IMCD) urea transporters, UT‐A1 and UT‐A3, are unable to concentrate their urine. It is not known whether this defect results from the absence of UT‐A1, UT‐A3, or both. Studies suggest a functional UTA1/ A3 heterodimer. To investigate, we generated a UT‐A1 gene that could not be spliced to produce UT‐A3, behind its original UT‐A promoter. We introduced this transgene into UT‐A1/A3 knock‐out (KO) mice to yield a mouse expressing UT‐A1 but not UT‐A3 (UT‐A1‐only mice). Western blot demonstrated UT‐A1 protein in inner medulla (IM) of UT‐A1‐only and wild‐type (WT) mice, but not in UT‐A1/A3 KO mice. UT‐A1 protein was not detected in brain, heart, colon, lung, liver, spleen, vas deferens, or testes of UT‐A1‐only mice. Immunohistology showed UT‐A1 staining only in the IM of the UT‐A1‐only mice. Basal urine osmolalities were similar in WT (2844 mOsm) and UT‐A1‐only mice (2508 mOsm); both were higher than UT‐A1/A3 KO (920 mOsm)(p<.05). Overnight water restriction increased urine osmolality similarly in WT (4469 mOsm) and UT‐A1‐only (3656 mOsm) mice; both were higher than UT‐A1/A3 KO (1365 mOsm)(p<.05). We conclude that mice expressing UT‐A1, but not UT‐A3, are able to concentrate their urine to similar levels as WT mice. This suggests UT‐A3 may not be essential for urine concentration and that the functional urea channel in the IMCD is not a UT‐A1/UT‐A3 heterodimer. Support:NIDDK
Modeling the effects of medullary blood flow regulation on pressure natriuresis
Authors: Moss Robert , Layton Anita
Published: June 2021

The regulation of medullary blood flow by the vasoactive decending vasa recta may play an essential role in pressure natriuresis. While the regulatory mechanism remains incompletely understood, and quantities such as the absolute medullary blood flow remain experimentally inaccessible, many factors involved in that regulation have been identified. We present a whole‐kidney model of water and sodium balance that encompasses the renal vasculature and a population of superficial and juxtamedullary nephrons, each of which has a separate juxtaglomerular apparatus and autoregulates autonomously. Vasoconstriction of the vasculature and the epithelial transport are regulated by plasma hormone levels. Model predictions are consistent with acute renal function curves obtained from in vivo studies of the rat under a wide range of physiological conditions. We use this model to investigate the effects of vascular vasoconstriction and medullary blood flow regulation on the kidney's ability to produce concentrated urine at high arterial pressures. These findings are evaluated against the known and hypothesized actions of the known regulatory mechanisms. This research was supported in part by NIH grant DK‐89066.
Postmenopausal response to angiotensin II‐induced hypertension is blunted during perimenopause: a study in the accelerated ovarian failure (AOF) model of menopause
Authors: Pollow Dennis , Perez Jessica , Booth Allyson , Constantopoulos Eleni , Konhilas John P , Brooks Heddwen L
Published: June 2021

A female's risk of developing hypertension (HTN) increases dramatically after menopause. This study aimed to investigate the onset of ANG II‐induced HTN in the AOF model of menopause (VCD model). The AOF model preserves a perimenopausal period in mice, which is increasingly recognized as a critical timeframe for the treatment and prevention of diseases. We hypothesized that ANG II‐infusion would elicit a differential response when administered in peri vs postmenopause and examined the cardiovascular and renal impact. Female VCD treated BL/6 mice (peri and postmenopause) received 800 ng/kg/min ANG II via osmotic mini‐pump for 10 days. ANG II elicited a significant increase in MAP in postmenopausal females (ANG/POST) vs cycling females (C 105 vs ANG 128 vs ANG/POST 143 mmHg, P<0.05). In contrast, there was no difference in MAP in the perimenopause study; ANG II increased MAP in cycling and PERI groups (~126 mmHg). AQP2 protein expression significantly decreased in the renal cortex of ANG/POST mice alone (C 100 vs ANG 98 vs ANG/POST 78%). Renal inflammation, measured by ICAM‐1and F4/80 staining, increased in ANG/POST vs all other groups. Cardiac collagen volume fraction significantly increased in ANG/POST vs ANG (C 0.36 vs ANG 1.36 vs ANG/POST 2.94%). Our data suggests that the perimenopause to menopause transition is a key stage in the loss of a female's protection against developing HTN, and renal and CV complications.