bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptation of bone and calcium metabolism to low dietary calcium (Ca) stress is affected by genetic background in mice
Authors: McCreedy Rebecca , Arges Alexandra , Fleet James C
Published: June 2021

We tested the hypothesis that Gene × Diet interactions influence adaptation of Ca and bone metabolism to low Ca intake using inbred mice. Male C57BL/6J (B6), DBA/2J (DBA), and PWK/PhJ (PWK) mice were fed diets containing adequate (0.5%) or low (0.25%) Ca levels from weaning until 3 mo (n=6–12 per group) when 45Ca absorption (Ca Abs) was assessed after an overnight fast (n=6 per group), serum was harvested for vitamin D metabolite levels, and femura were fixed for DEXA analysis of bone mineral density (BMD). Significant differences between the lines on the 0.5% Ca diet were observed for body weight (B6>DBA>PWK), BMD (DBA>B6>PWK), serum 25 hydroxyvitamin D (B6>DBA>PWK), serum 1,25 dihydroxyvitamin D (1,25 D; DBA>B6=PWK), and Ca Abs (B6>DBA=PWK). Ca restriction reduced BMD only in DBA mice (10.6% lower) and this was partly explained by their inability to increase serum 1,25 D and Ca Abs; low Ca diet increased serum 1,25 D and Ca Abs by 70% and 60%, respectively in B6 mice and by 97% and 11%, respectively in PWK mice. These data suggest there are genetic factors influencing basal levels of vitamin D and calcium metabolism in inbred mouse lines as well as the adaptation of Ca metabolism to dietary Ca restriction in DBA mice. Future forward genetic approaches will be necessary to identify the genetic variation responsible for these physiological differences. Supported by NIH Award DK054111 and funds from Purdue University
The influence of Glutathione‐S‐transferase(GSTs) polymorphisms on the level of oxidative DNA damage, antioxidant status and lipid profiles in healthy Korean adults
Authors: Jo Hye Ryun , Lee Hye‐Jin , Han Jeong hwa , Cho Mi Ran , Park Yoo Kyoung , Park Eunju , Kang Myung‐Hee
Published: June 2021

Human glutathione‐S‐transferases (GSTs) are known as phase □ enzymes involved in the detoxification to protect oxidative stress. This study compares the contribution of GSTT and GSTM genetic polymorphism on the susceptibility to oxidative damage or to antioxidant status on healthy subjects depending on their smoking status. The degree of DNA damage in smokers (n=48) were not significantly different than that of non‐smokers(n=197). Similarly, the levels of total radical trapping antioxidative potential(TRAP), erythrocyte SOD, GST‐Px and catalase showed slight increase in the GSTT1, GSTM1 null type, but, was not significantly different. Plasma HDL‐Chol was significantly higher in the GSTM1 null type(p<0.05), while the other parameters were not different. In non‐smokers, GSTT1 null genotype had significantly higher DNA damage than the wild type(p<0.05). Plasma TRAP and the levels of antioxidant enzymes did not show any significant difference depending on the genotype. When all these effect was adjusted with smoking status, GSTM1 wildtypes and GSTT1 null types showed lower overall oxidative stress. (This study was supported grant, 2009‐0069893, from the National Research Foundation of Korea)
Influence of honey versus sucrose on glucose, insulin and lipid responses in mice
Authors: Nemoseck Tricia , Cole Sarah , Petrisko Yumi , Hong Mee Young , Kern Mark
Published: June 2021

We previously reported that honey may reduce weight gain and adiposity compared to sucrose in adult rats. Our goal was to determine the influence of honey versus sucrose on adiposity and plasma concentrations of glucose, insulin and lipids in weanling mice. Thirty male ICR mice (34.0 ± 2.4g) were equally divided into two groups and fed ad libitum one of two isoenergetic diets differing only in a portion of the carbohydrate provided. Diets contained 20% carbohydrate (by weight of total diet) from either clover honey or sucrose. After 34 days, fat pads were excised and blood was collected. Weight gain and fat pad weights were similar (p>.05) between mice fed honey and sucrose. Non‐fasting plasma glucose and fasting glucose and insulin levels were lower (p≤.05) by 11%, 21% and 33%, respectively, for honey‐fed mice compared to sucrose‐fed mice. Total cholesterol was 18% higher (p≤.05) for mice fed honey versus sucrose: however, no differences (p>.05) in triglyceride or HDL‐cholesterol levels were detected. These results suggest that in comparison to sucrose, consuming a diet containing honey may promote better glucose control but worse cholesterol concentrations while not altering adiposity in young, growing mice. More research is necessary to better understand the possible health influences of honey versus refined sugars following acute and long‐term exposures.

Sponsored by American Heart Association
Postprandial energy availability with three popular diets during weight maintenance after weight loss
Authors: Walsh Carolyn Olson , Ebbeling Cara , Swain Janis , Feldman Henry , Ludwig David
Published: June 2021

We compared the effect of three popular diets on postprandial (PP) metabolism in weight loss maintenance. Participants (n=8 overweight/obese young adults) were fed standard hypocaloric diets to produce 10–15% weight loss, then isocaloric low fat (LF), low glycemic index (LGI) and very low carbohydrate (VLC) diets, each for 1 month in a randomized cross‐over fashion. Participants were studied before and every 30 minutes for 5 hours after test meals. Endpoints were metabolic fuels, energy availability (EA, combined energy density of glucose, free fatty acids [FFA] and & beta‐hydroxybutyrate [BHB]), hormones, metabolic rate (MR), and hunger. Data were analyzed by repeated‐measures ANOVA, with contrasts to compare EA in early and late PP periods. There were significant (p<0.05) diet‐time interactions for glucose, FFA, BHB, insulin, glucagon, and MR, but not cortisol, epinephrine, or hunger. EA differed negligibly during the early PP period (p=0.99) but significantly in the late period (p<0.0001), being lower on LF than LGI or VLC. Future work will examine implications of a LF diet limiting late PP EA for risk of weight regain. Funding: Harvard Medical School, Doris Duke Charitable Foundation, and NIDDK.
Study of Dietary Reference Intakes of Protein for Chinese Male Youths with Labeled Leucine and Lysine
Authors: YANG Xiaoguang
Published: June 2021

Six experimental diets of different designed protein levels in Chinese diet were consumed by 20 healthy male youths divided into two groups in three continuing 7‐day cycle separately. After 5 days¡ adaptation, intravenous transfusion of stable isotope labeled leucine (13C) and lysine(15N) was administrated in 3 hours. The abundances of 13CO2 and 15N‐urea in the samples were determined, then computed the flux and oxidation rate of leucine and lysine. We explored the protein requirement by constructing the two phase linear regression equations between protein intakes and amino acid oxidation rate and determined the regression curve breakpoint. We adopted the largest value of 0.83g/kg/d among all three protein requirements determined by three regression curves as the average physiological requirements for our study population, and the recommended nutrient intake of 0.96g/kg/d for protein.
Practices of obstetricians regarding early mother‐to‐newborn skin‐to‐skin contact, early initiation of breastfeeding and delayed cord clamping
Authors: Begum Khadija , Dewey Kathryn G.
Published: June 2021

Early mother‐to‐newborn skin‐to‐skin contact (SSC) promotes early initiation of breastfeeding (EIBF), which in turn decreases neonatal mortality. Delayed cord clamping (DCC) improves iron status of infants, but may be erroneously regarded as incompatible with early SSC. Despite international recommendations for these evidence‐based practices, data are lacking on their adoption by obstetricians. We conducted a survey of 142 obstetricians from 60 countries who attended the 2009 FIGO World Congress of Gynecology and Obstetrics. Although early SSC and BF within 1 h of birth were facilitated by 79% and 82%, respectively, of the obstetricians, adherence to DCC practice was lower (12%).

World region
Early SSC (%)
BF within 1 h (%)
DCC ≥ 3 min (%)

Africa
81
87
5

Americas
87
80
20

Eastern Mediterranean
39
46
0

Europe
90
88
27

Southeast Asia
60
90
5

Western Pacific
91
73
0

Total
79
82
12

Significant regional variation was observed for each of these practices, with p values of .001, .014 and .009 respectively for early SSC, EIBF and DCC. Facilitation of early SSC was > 90% in both Europe and Western Pacific region, but adherence to DCC was more common in Europe. We conclude that DCC has not been well integrated into current obstetric practice. Identification of the obstacles preventing integration and implementation of these three practices is needed, especially in regions with high neonatal morbidity and mortality.

Supported by UC Davis
The International Milk Genomics Consortium Web Portal
Authors: Lemay Danielle G , Lange Matthew C , Crook Sean C , Sela David A , Lefèvre Christophe , Church Philip , Pasin Gonca , Hauser Michael A , van Arendonk Johan A.M. , Boichard Didier , Mather Ian H , Martin Patrice D , Moore Stephen S , Neville Margaret C , Rijnkels Monique , Singh Kuljeet , Stanton Catherine , Williamson Peter , German J. Bruce
Published: June 2021

The International Milk Genomics Consortium (IMGC) was established to increase communication and collaboration among milk and mammary scientists, to accelerate research into the biological processes underlying milk, and to improve understanding of the health traits conferred to mother and offspring. The IMGC Web Portal (http://www.milkgenomics.org) is a publicly available resource in which milk and mammary genomic, transcriptomic, proteomic, and glycomic data from various organisms have been curated, integrated, and linked with external databases and tools. Users can upload their own data and control data access to facilitate collaborative projects prior to and after publication. Funded by the IMGC.
Job performance of school dietitians was different than their percived job importance
Authors: Khil Jinmo , Kim Hye‐Kyoung
Published: June 2021

This study conducted job analysis of school foodservice dietitian through the perceived job importance and level of performance in Gwangju and Jeonnam areas. Of 646 questionnaires, 244 cases were analyzed by SPSS 12.0 and frequency, t‐test, ANOVA were performed. We compared the recognition of job performance and the perceived job importance by the school classification. There are significant differences between the recognition of job performance and perceived job importance among elementary school (p<0.0001) and middle school (p<0.0001), but not in high school dietitians in the area of nutrition management. Elementary school dietitians recognized significantly higher importance of purchasing management than their actual job performances (p<0.0001). All level of school dietitians recognized the importance of nutrition education, however, the mean value of actual job performance were lower compared to the other duties of school dietitians (p<0.0001). These results suggest that school dietitians recognized the importance of their duties, however the actual performances are not always match the perceived importance of tasks.
Iron deficiency and iron deficiency anemia among pregnant women in Kuwait
Authors: Ahmed Faruk , Al‐Sumaie Mona A
Published: June 2021

This cross‐sectional study investigated the prevalence of iron deficiency and iron deficiency anemia among pregnant women in Kuwait. It also examined the association of various factors with iron status. A total of 465 women, aged 18–47 years, of 4–39 weeks gestation attending maternity clinics in six governorates in Kuwait participated in the study during January–March, 2009. Socio‐demographic, pregnancy related and dietary information were collected. Blood hemoglobin (Hb) and serum ferritin (SF) concentrations were determined. The prevalence of anemia (Hb<11.0 g/dL) among the participants was 24.1% and 55% had depleted iron stores (SF<12.0 μg/dL). Of all anemic subjects, 73% had iron deficiency anemia (Hb<11.0 g/dL and SF <12.0 μg/dL). There was a significant positive association between Hb and SF levels (r=0.245; p=0.001). Significant positive correlations were observed between SF and education level of the participants, consumption frequency of white bread and meat sandwich, while there was a negative correlation with parity, gestational age and consumption frequency of brown bread, tea and coffee. In conclusion, iron deficiency is highly prevalent among Kuwaiti pregnant women, and nearly three‐fourths of the anemia can be explained by iron deficiency. Various factors including diet may contribute to the poor iron status of these women. Funded by Kuwait University, Research Grant No: WF01/08.
B12 vitamin and folate nutritional status in Mexican children under five years old.
Authors: Cuevas‐Nasu Lucia , Shamah‐Levy Teresa , Villalpando Salvador , Gómez‐Humarán Ignacio Méndez
Published: June 2021

Objective

To evaluate the prevalence of B12 vitamin and folate deficiency in Mexican population under five years old.

Methods

the data used in the present study was obtained from the National Health and Nutrition survey 2006. Venous blood samples were collected from a subset composed by 2674 randomly selected children (weighted 7,796,342 children). Deficiencies were categorized as Vitamin B12 <203 pg/mL, folate <4ng/mL. Logistic regression models were tested, adjusting by age, sex, socioeconomic status and to be beneficiary of the “Oportunidades” governmental program.

Results

B12 vitamin deficiency was 10%; urban localities (7.4%) vs rural localities (12.2%), the South Region of the country shown the highest prevalence of deficiency (13.7%) vs North and Center. Socioeconomic level, dietary fiber and age were all factors positively associated with B12 deficiency. Folate deficiency prevalence was 2.9 % at national level, South Region presented the highest prevalence (3.5%) in contrast with the North 2.3% and Center 2.5%.

Conclusions

B12 Vitamin and folate deficiency in children under 5 years old was higher in rural areas and the south region of the country were the poorest families inhabit. Due to this to carry out actions like fortify foods focused in this age group that prevent deficiencies of this micronutrients must be a first concern in order to promote a healthy growth and development.
Gestational weight gain knowledge among low‐income pregnant Latinas
Authors: Hromi‐Fiedler Amber , Bermúdez‐Millán Angela , Chapman Donna , Segura‐Pérez Sofia , Damio Grace , Pérez‐Escamilla Rafael
Published: June 2021

The objective of this study was to describe the knowledge about gestational weight gain among low‐income pregnant Latinas (N=136). Based on current IOM guidelines, over 55% of women were overweight or obese before pregnancy. Over 45% of women gained excessive gestational weight during pregnancy. When asked their feelings about how much weight they had gained during pregnancy, almost half reported they felt they had gained too much weight. Only 26% of participants knew the recommended amount of weight they should gain during pregnancy, with 31% reporting an amount less than the recommended, and 29% reporting that they didn't know how much to gain. Only 55% of women reported that a health care provider discussed gestational weight with them, however 50% of those women reported that they weren't specifically told the amount of weight they should gain. These findings show that excessive gestational weight gain is prevalent among low‐income Latinas, yet they are not being advised on appropriate gestational weight gain by health care providers. Interventions targeting dissemination of appropriate gestational weight gain recommendations by health care providers are needed. Funded by Connecticut NIH EXPORT Center for Eliminating Health Disparities among Latinos (NIH‐NCMHD Grant # P20MD0017650).
Reproducibility regarding the age of introduction of complementary foods to infants as self‐reported by urban and rural low‐income mothers in Guatemala
Authors: Soto María José , Campos Raquel , Hernández Liza , Vossenaar Marieke , Solomons Noel W
Published: June 2021

Background

Many published reports in complementary feeding practices rely on a 1‐time maternal response regarding introduction of foods to the breast‐fed infant's diet.

Objective

To determine the consistency over 3 separate administrations of the responses to a questionnaire regarding first introduction of 10 selected complementary foods.

Methods

As part of a larger study among 6–12 mo old infants (n=50, rural; n=64 urban), mothers were interviewed on 3 occasions within an interval of 2 to 14 wks, and asked the age of their infant on introduction of: Incaparina, oatmeal, rice, fruits, vegetables, white roll, sweet roll, prepared baby food, potato and coffee. A score of 3 (full repetition), 2 (2 of 3 consistent) and 0 (3 distinct answers) was given for each food (“food score”), and summed across all foods for a “maternal score”.

Results

The mean maternal scores for overall reproducibility were 20±6 (urban) and 22±5 (rural), out of a maximal score of 30 (p=0.01). The same 4 foods (white rolls, sweet rolls, baby food, and coffee) were the most reproducible for both settings.

Conclusions

The high degree of consistency in the responses adds confidence to the proposition that published data on age of complementary food introduction is generally valid.
Urinary phytoestrogen biomarkers in the U.S. population: findings from the National Health and Nutrition Examination Survey (NHANES 1999–2004)
Authors: Rybak Michael E. , Jain Ram B. , Pfeiffer Christine M.
Published: June 2021

Phytoestrogens are plant‐derived compounds with weak estrogen‐like behavior. Their consumption is thought to reduce the risk of hormone‐dependent cancers (e.g., breast and prostate). We analyzed data from the National Health and Nutrition Examination Survey (NHANES) on urinary levels of phytoestrogenic isoflavones [daidzein (DAZ), genistein (GNS), equol (EQU), O‐desmethylangolensin (DMA)] and lignans [enterolactone (ETL) and enterodiol (ETD)] from 1999 to 2004. Results were stratified by age, sex, race/ethnicity, fasting time, smoking status and serum C‐reactive protein (CRP). Weighted means and selected percentiles were determined for unadjusted and creatinine normalized data. Means were also calculated using a least‐squares model to adjust for covariate main effects for significance testing purposes. Phytoestrogen levels tended to be highest in the youngest age categories and higher in females vs. males, though these differences were not always statistically significant. Significant differences were observed among race/ethnicity categories for several phytoestrogens. EQU, DMA, ETL and ETD levels were significantly higher in non‐smokers vs. smokers (p<0.001). The lignans also showed significant differences (p<0.001) among CRP concentration and fasting time categories. This large data set provides reference ranges by age, sex, and race‐ethnicity.
Socioeconomic status and measures of dietary recall accuracy for fourth‐grade children
Authors: Baxter Suzanne Domel , Guinn Caroline H , Royer Julie A , Hardin James W , Mackelprang Alyssa J , Devlin Christina M , Smith Albert F
Published: June 2021

We investigated the relationship between children's socioeconomic status (SES) and their dietary recall accuracy. We categorized SES by eligibility for school meals as free = low SES, reduced price = middle SES, and full price = high SES. Each of 374 fourth‐grade children (96% Black) was observed eating school breakfast and school lunch, and then interviewed to obtain a 24‐hour dietary recall that included the 2 observed meals. (Data were collected in 17, 17, and 8 elementary schools during the 2004–05, 2005–06, and 2006–07 school years in 1 district.) We ran ANOVA for each of 5 measures: omission rate and intrusion rate (2 measures of reporting error for food items), total inaccuracy (a measure that combined reporting errors for food items and amounts [in servings]), correspondence rate (a measure of reporting accuracy for energy), and inflation ratio (a measure of reporting error for energy). Only for total inaccuracy did SES groups differ significantly (p = 0.0298): The least‐squares means were lower (better) for middle SES at 4.9 servings than low SES at 6.3 servings (p = 0.0487), and for high SES at 5.2 servings than low SES (p = 0.0596), but did not differ significantly for middle SES and high SES (p = 0.7397). A limitation of these analyses is the homogeneity of children by SES as categorized by eligibility for school meals: 88% of children were low SES, 5% were middle SES, and 7% were high SES. Funded by R01HL074358.
Sex differences in response to a Mediterranean diet on cardiovascular risk profile
Authors: Bédard Alexandra , Riverin Mélissa , Dodin Sylvie , Corneau Louise , Lemieux Simone
Published: June 2021

Objective

To investigate differences between men and women with regard to changes in metabolic parameters associated with cardiovascular risks in response to a 4‐week eucaloric controlled nutritional intervention based on the traditional Mediterranean diet.

Methods

Participants were men and premenopausal women who had a slightly elevated plasma LDL‐cholesterol concentration (between 3.4 and 4.9 mM) and at least one factor of the metabolic syndrome. During the intervention, all foods and drinks concordant with the traditional Mediterranean diet were provided to participants. Metabolic parameters were measured before and after the controlled intervention. These preliminary analyses included data from 23 men and 16 women.

Results

Compared with baseline, plasma concentrations of total cholesterol, LDL‐cholesterol and apolipoprotein‐B significantly decreased in both men and women (respectively 9%, 10% and 9% for men and 9%, 9% and 12% for women; P<0.05). Significant decreases in area under the insulin curve and a significant improvement in insulin sensitivity were observed only in men (P<0.05).

Conclusion

According to our preliminary results, consuming a traditional Mediterranean diet leads to significant changes in plasma lipid‐lipoprotein profile in both men and women. Significant improvements in plasma glucose–insulin homeostasis were observed, but in men only.

Supported by CIHR and HSFC
Effect of almond consumption on the serum fatty acid profile: a dose response study
Authors: Kendall Cyril WC , Nishi Stephanie , Yoon Ana‐Maria , Esfahani Amin , Bazinet Richard P , Lapsey Karen G , Jenkins David JA
Published: June 2021

Background

Studies indicate that diets high in monounsaturated fatty acids (MUFA) can improve the blood fatty acid profile, by elevating oleic acid concentrations, and as such, relate to a decreased risk of coronary heart disease (CHD). Almonds are a good source of MUFA.

Objective

To assess the dose‐response effect of almonds compared to low‐fat muffins on the blood fatty acid profile and blood lipid risk factors of CHD in hyperlipidemic subjects.

Design

In a randomized controlled crossover study, 27 hyperlipidemic men and women consumed three iso‐energetic (mean 423 kcal/d) supplements in one‐month phases. The supplements consisted of full‐dose almonds (50–100g/d), half‐dose almonds with half‐dose muffins, and full‐dose muffins. Fasting blood was obtained at weeks 0 and 4 of each treatment.

Results

On both the half‐ and full‐dose almond supplements, there were significant increases in the oleic acid fraction of the blood lipid fractions. In addition, significant reductions were seen, respectively, for Total‐C (P=0.035; P=0.002), LDL‐C (P=0.021; P<0.001), Total:HDL‐C (P=0.003; P<0.001) and LDL:HDL‐C (P=0.002; P<0.001) with increases in HDL‐C (P=0.021; P=0.014).

Conclusion

Almond consumption significantly increased the oleic acid content of the blood lipid fractions and significantly improved blood lipid risk factors for CHD.

(Funded by the Almond Board of California)
Pathologic changes in breast cancer after anti‐estrogen therapy
Authors: Samarnthai Norasate , Elledge Richard , Huang Jian , Massarweh Suleiman , Yeh I‐Tien
Published: June 2021

Estrogen receptor positive breast cancers are commonly treated with anti‐estrogen therapy. However, little is known about the pathologic changes in breast cancers after anti‐estrogen therapy. This study details the histologic alterations of estrogen receptor positive breast cancers treated by anti‐estrogens in combination with gefitinib, an anti‐EGFR agent given to overcome endocrine resistance. Estrogen receptor positive tumors from 9 post‐menopausal women were studied. Patients received anastrazole, fulvestrant, and gefitinib for 4 months. Core needle biopsies were performed at day 1 and day 21, and tumors were completely excised if tumors were operable at day 112. The histologic findings were correlated with clinical responses defined by RECIST criteria. Median age was 67 years and median tumor size was 7 cm. Following treatment, all tumors had evidence of degenerative changes including smudged nuclei, decreased nuclear size, intranuclear vacuoles, vacuolated cytoplasm, and increased cellular discohesion. Increased tubule formation and intracytoplasmic lumina were seen in 6/9 cases (66.7%), and decreased mitotic rate was demonstrated 5/9 cases (55.6%). In the partial response group, there was tumor shrinkage and increased stromal fibrosis. These findings indicate increased differentiation of the cells with anti‐estrogen therapy and correlate with clinical response.
Functional Evaluation of a 3‐D Nerve Construct Utilized for Repair of a Critical Nerve Defect
Authors: Adams Aaron Michael , Kostrominova Tatiana Y , Larkin Lisa Marie
Published: June 2021

Nerve grafts are often required to replace tissue damaged by disease, surgery, or extensive trauma. Limitations associated with grafting such as graft availability, donor site morbidity, and immune rejection have led investigators to develop strategies to engineer nerve tissue. The purpose of our research was to engineer a scaffold‐less 3‐D engineered nerve construct that would be functionally equivalent to native nerve. As per our labs' previously established protocol, fibroblasts isolated from F344 rat Achilles tendon and neural cells from E15 fetal spinal cords were co‐cultured and engineered into 3‐D constructs. Following 3‐D formation, neural cells oriented along the axis of strain. The functionality of a nerve is measured by its ability to conduct an electrical signal along the length of the cell axon or nerve conduction velocity. To establish an in vivo standard, conduction velocities were measured in neonatal rats ranging from 7 – 28 days. The in vivo velocities peaked at 28 days when recordings reached the expected adult conduction velocity of 16 m/s. One week after establishing a 3‐D conformation, nerve constructs were utilized in a 2 cm nerve defect repair. Following a 2 month recovery, conduction velocities and target muscle mechanical properties were evaluated. Our results suggest that our scaffold‐less 3‐D engineered nerve construct may be a viable strategy for nerve repair. Supported by R01 AR054778‐02 and gift from the Barbara & Richard Raynor Medical Foundation.
L‐4F Rescues the Metabolic Syndrome Phenotype of HO‐2 Null Mice via Insulin, Adiponectin, & LKB1 Signaling Pathways
Authors: Angevine Kristine Rose , Burgess Angela P , Vanella Luca , Kim Dong Hyun , Sodhi Komal , Peterson Stephen J , Abraham Nader G , Mensah‐Osman Edith
Published: June 2021

The development of apoA‐I mimetic peptides, such as 4F, has been shown to decrease ROS and adiposity. Studies suggest that CYP‐derived epoxyeicosatrienoic acids (EETs) decrease adiposity and participate in vascular protection. We hypothesized that the apolipoprotein mimetic peptide, L‐4F, may reduce adiposity and oxidative stress in mice lacking heme oxygenase‐2 genes, which displays obesity and metabolic syndrome via an increase in EET synthesis.

Wild type and HO‐2−/− Mice were divided into three groups: Vehicle treated, L4‐F treated, and L4‐F + SnMP (antagonist to HO‐1), and injected with 2mg/kg via IP daily for 8 weeks.

L‐4F‐mediated increases in EETs levels were associated with increases in adiponectin, pLKB‐1, pAMPK and NO levels in HO‐2−/− mice. Suppression of HO activity by administration of SnMP to L4‐F‐treated HO‐2−/− mice reverses adiposity and decreases adiponectin levels. The anti‐obesity effects of L‐4F are manifested by a decrease in visceral fat content with reciprocal increases in adiponectin, LKB‐1 and pAMPK.

The increase in adiponectin, LKB‐1 and pAMPK resulted in restoration of vascular dysfunction as seen by a decrease in adiposity and improved insulin sensitivity, suggesting the L4‐F may have beneficial effects on obesity, diabetes, and atherosclerosis.
Improvement of blood rheology by product GRTC in a Metabolic Syndrome aging model
Authors: Yang Jieying , Tan Ningzhi , Zhang Yan , Zhao Chunsheng , Zhu Jia‐Shi
Published: June 2021

Long‐term high‐calorie diet results in metabolic syndrome causing atherosclerosis and shortens the lifespan, due to mitochondria dysfunction, impairment of glucose, lipids and energy metabolisms and increases in oxidative stress and protein glycation (FASEB J 23:578.15, 2009). The atherosclerotic, oxidative and glycation pathology may impair RBC's ability in deformation and aggregation, causing increased blood viscosity and vascular dysfunctions. The benefits of the proprietary product GRTC include antioxidant, improving mitochondria functions on glucose‐lipid‐energy metabolisms, anti‐fatigue and endurance enhancement, and lifespan extension. We further tested the effect of GRTC in lowering blood viscosity in metabolic syndrome rats with elevated plasma AGEs. After on a high‐calorie diet for 44 wks, aged rats with impaired oral glucose tolerance were randomized based on their plasma AGEs fluorescence values into 4 groups, either continuing on the diet (controls) or consuming the same diet mixed with GRTC at a dose of 0.2, 0.4 or 0.8 g/kg. Blood viscosity was examined after 28 wks of GRTC. Compared to controls, GRTC at 0.2g/kg reduced blood viscosity and GRTC at 0.2 & 0.8g/kg reduced the AUC of blood viscosity in rats (p<0.05), with improvement of both high‐shear and low‐shear viscosity. Our findings indicate the benefits of GRTC in hemorheology and reduced risks in vascular diseases.
TNF‐derived TIP peptide ameliorates High Glucose (HG)‐induced Arginase (ARG) mediated Endothelial Dysfunction (ED) via inhibiting PKC‐α activation
Authors: Romero Maritza Josefina , Yang Guang , Chandra Surabhi , Sridhar Supriya , Lucas Rudolf , Caldwell Robert William
Published: June 2021

During diabetes, elevated ARG activity causes ED by competing with NO synthase (eNOS) for their common substrate L‐arginine. HG levels activate protein kinase C (PKC)‐α, implicated in impaired endothelial vasorelaxation and hyperpermeability. PKC‐α activates NADPH oxidase (NOX)‐dependent ROS generation and the small GTPase RhoA, upstream to ARG activation. We hypothesize that during diabetes, HG‐induced PKC‐α activation causes reduced NO production and endothelial hyperpermeability via NOX‐RhoA dependent ARG activation, which is prevented using TIP peptide. Indeed, our results show that TIP peptide (50 μg/mL) inhibits HG (30 mM)‐induced PKC‐α activity (7 fold vs ctrl‐5mM glucose, 30 min), ROS generation (160% of ctrl) and p115 Rho GEF membrane translocation (2h) in aortic endothelial cells (AEC). Moreover, HG‐induced ARG activation (24h), impaired NO production (55% of ctrl) and endothelial hyperpermeability, were also prevented by TIP peptide. ARG inhibitor BEC (100 μM) also preserved endothelial barrier function in HG‐treated AEC, indicating a central role for ARG in ED. Compared to conventional PKC‐α inhibitors, TIP peptide does not demonstrate any cytotoxicity in AEC after 24h treatment. In conclusion, these results indicate that substances able to blunt HG‐induced PKC‐α activation, such as TIP peptide, might be useful in treating diabetes‐associated ED. (Supported in part by NHLBI 70215).
Effects of PETN and ISDN on vascular dysfunction and oxidative stress in an experimental model of Diabetes
Authors: Knorr Maike , Oelze Matthias , Schuhmacher Swenja , Wenzel Philip , Hochmuth Christian , Steven Sebastian , Heeren Tjebo , Stalleiken Dirk , Muenzel Thomas , Daiber Andreas
Published: June 2021

Background

Vascular complications in diabetes mellitus (DM) are associated with increased reactive oxygen species (ROS) formation. Therefore we tested, if treatment with PETN, which has been shown to induce the antioxidant enzyme heme oxygenase‐1, improves ROS formation and vascular function in a diabetic rat model.

Methods/Results

DM was induced by a single i.v. injection of streptozotocin (STZ, 60mg/kg) in male Wistar rats. After 8 weeks of PETN (15mg/kg/d) vs. isosorbid dinitrate (ISDN, 10 mg/kg/d) vs. isosorbide‐5‐mononitrate (ISMN, 75mg/kg/d) treatment, rats were sacrificed. STZ‐treated rats showed an increase in vascular and cardiac ROS production, detected by HPLC. Endothelial function, measured by isometric tension studies, was impaired. PETN therapy improved almost all parameters more efficiently than ISDN, while ISMN had no protective effects. Some rats were treated with insulin (2.5U/d). Insulin normalized all parameters completely proving that STZ‐induced vascular dysfunction depends on hyperglycemia but not on unspecific toxicity of the compound.

Conclusion

In diabetic rats, PETN showed more pronounced antioxidative effects than ISDN. Insulin normalized all parameters and thereby identified the underlying mechanism of cardiovascular dysfunction in STZ‐induced DM to strictly depend on insulin levels highlighting the importance of this model.
A Novel Antagonist for the Thromboxane A2 Receptor
Authors: Khasawneh Fadi T , Ting Harold J
Published: June 2021

Despite the well‐documented involvement of thromboxane A2 receptor (TPR) signaling in thrombotic diseases, there are currently no antagonists available for clinical use. To this end, previous work has defined the C‐terminus of the second extracellular loop (C‐EL2) of TPR as the ligand binding site, and mapped the amino acids which mediate ligand interaction. Since EL2 contains the ligand binding pocket, we hypothesized that an antibody (referred to as C‐EL2Ab) that targets this domain would exhibit biological activity. On this basis, we investigated the capacity of C‐EL2Ab to block TPR‐dependent platelet aggregation. Our initial results demonstrated the C‐EL2Ab blocked human and mouse platelet aggregation triggered by the TPR agonist U46619, in a dose‐dependent fashion; whereas control experiments revealed that it did not produce any detectable effects on aggregation by ADP. Together, these findings suggest that C‐EL2Ab acts as a selective antagonist for TPRs. Consistent with this notion, we found that C‐EL2Ab displaced a radio‐labeled TPR antagonist (i.e., [3H]SQ29,548) from its platelet TPR binding sites. Finally, using ex vivo experimental settings, it was found that intravenous tail injections of C‐EL2Ab resulted in significant blockade of mouse platelet aggregation by U46619, but not by ADP.

In summary, these studies show that C‐EL2Ab dose‐dependently blocks platelet aggregation induced by the TPR pathway, under both in vitro and ex vivo conditions, and that these effects are mediated via direct interaction with the receptor protein. Collectively, these results clearly demonstrate that C‐EL2Ab exerts TPR‐specific anti‐platelet effects, thus making it the first function‐blocking antibody against these receptors. Moreover, the identification of a functionally active TPR sequence will significantly aid molecular modeling study predictions for organic derivatives which possess in vivo activity.
Dysfunction of endothelial and smooth muscle cells in small arteries of a mouse model of Marfan syndrome
Authors: Syyong Harley , Chung Ada WY , Yang Clarice HH , van Breemen Cornelis
Published: June 2021

Marfan syndrome, a connective tissue disorder caused by mutations in FBN1 encoding fibrillin‐1, results in life‐threatening complications in the aorta, but little is known about its effects in resistance vasculature. Second‐order mesenteric arteries from mice at 3, 6, and 10 months of age heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1C1039G/+) were compared with those from age‐matched control littermates. Stress‐strain curves indicated that arterial stiffness was increased at 6 and 10 months of age in Marfan vessels. Isometric force measurement revealed that contraction in response to high potassium‐induced membrane depolarization was significantly decreased in Marfan vessels at all ages, while both phenylephrine‐induced contraction and frequency of Ca2+ oscillations was reduced by at least 40% from 6 months onward. In addition, both endothelium‐dependent and endothelium‐independent relaxation to acetylcholine and sodium nitroprusside, respectively, was also reduced starting at 6 months of age. We conclude that pathogenesis of Marfan syndrome in resistance‐sized arteries increases stiffness and impairs vasomotor function. This work was funded by CIHR of Canada.
Characterization of the relaxant response to equilin in rat mesenteric arteries
Authors: Filgueira Fernando , Lobato Nubia , Ceravolo Graziela , Dantas Ana Paula , Fortes Zuleica , Webb Clinton , Tostes Rita , Carvalho Maria Helena
Published: June 2021

AIM

Premarin, the most widely used hormone replacement therapy in the USA, represents a complex mixture of at least 10 conjugated equine estrogens. Equilin (EQ – 24%) and estrone (E1 – 48%) are the most abundant of these components. However, their effects on vascular function have not been studied in detail. This study aimed to investigate the direct relaxing effects of EQ, E1, 17α‐estradiol (17α‐E2) and 17β‐estradiol (17β‐E2) in resistance mesenteric arteries from intact (INT) and ovariectomized (OVX) spontaneously hypertensive rats (SHR).

METHODS AND RESULTS

EQ and 17β‐E2 induced similar concentration‐dependent relaxation of rat mesenteric arteries (100% and 90%, respectively). 17α‐E2 and E1 only elicited a maximum relaxation of 56% and 41%, respectively. Similar relaxant responses were obtained in arteries from INT and OVX groups. EQ and 17β‐E2‐induced relaxation is acute, nongenomic, and independent of the endothelium or estrogen receptors. Inhibitors of K+ channels and signaling pathways mediated by adenylyl cyclase, guanylyl cyclase, PKA and PKG did not interfere with the relaxation to these compounds. EQ and 17β‐E2 blocked Ca2+ and Bay K 8644 (L‐type Ca2+ channel activator)‐induced contraction in the presence of KCl.

CONCLUSION

EQ and 17β‐E2 act on vascular smooth muscle inhibiting Ca2+ entry via L‐type Ca2+ channels. EQ may be protective against cardiovascular diseases. FAPESP,NIH(HL074167).
Vascular Endothelial Growth Factor (VEGF) Inhibitors Induce Hypertension, Afferent Arteriolar Dysfunction, and Glomerular Injury
Authors: Nagasawa Tasuku , Shaw Sean M , Walsh Katie A , Meyer Jessica L , Shaw Mary Cherian , Imig John D
Published: June 2021

VEGF plays a role in signaling and regulating tumor progression and metastasis via angiogenesis. Inhibition of angiogenesis by targeting VEGF signaling has proven to be a successful anticancer strategy for solid tumors. Unfortunately, hypertension and renal toxicity are common side effects of anti‐VEGF therapy. Moreover, the mechanisms by which VEGF inhibitors (VEGFi) exert these unwanted effects are not fully understood. The aim of this study is to investigate blood pressure regulation, vascular function and glomerular injury in animals treated with VEGFi. Rats were fed a high salt diet and treated with the VEGFi, Sorafenib or Sunitinib (20mg/kg/d) for 4 weeks. Rats were implanted with telemetry transmitters to measure blood pressure. At the end of the 4‐week period the afferent arteriolar response to ATP was measured and the second kidney processed for histology. Blood pressure was increased by 4 weeks of Sorafenib (151 □} 3 mmHg) or Sunitinib (129 □} 7 mmHg) compared to controls (107 □} 11 mmHg). Afferent arteriolar responses to ATP were attenuated by >50% in the VEGFi treated groups. Urinary albumin excretion, an indicator of renal injury, increased in the VEGFi treated groups. VEGFi treated rats also demonstrated a 3‐fold increase in the glomerular injury score.These results demonstrate that VEGFi, Sorafenib and Suninitb, increase blood pressure, as well as, cause vascular dysfunction and glomerular injury.
Contingent Methamphetamine Administration Decreases Dopamine and Vesicular Monoamine‐2 Transporter Function
Authors: McFadden Lisa M , Vieira‐Brock Paula L , Stout Kristen A , Nielsen Shannon M , Wilkins Diana G , Hanson Glen R , Fleckenstein Annette E
Published: June 2021

Methamphetamine (METH) is a highly addictive drug with the potential for long‐term health consequences. Although it has been reported in rodent models that METH can have detrimental effects on striatal dopaminergic neurons using non‐contingent dosing regimens, relatively little research has evaluated the effects of METH on dopaminergic neurons using a contingent dosing regimen. Thus, the current study examined if METH self‐administration alters dopamine (DA) transporter (DAT) and vesicular monoamine transporter‐2 (VMAT‐2) function in a manner similar to that caused by non‐contingent administration. Following food training and jugular vein catheter implantation, male rats were given 4 h of access to either 0.06 mg/infusion of METH or saline using a FR1 schedule for 5 d. Rats were sacrificed 1 h after the final session. Results revealed both decreased DAT and VMAT‐2 function in METH compared to saline‐treated controls in striatal tissue. Overall, these results suggest that contingent METH treatment decreases monoaminergic transporter function. The relationship among pressing behavior, METH/amphetamine levels and transporter function will be discussed.

Supported by: DA09407, 019447, 013367, 00869, 11389, 04222, 00378
The actions of piperidine alkaloids at fetal muscle‐type and autonomic‐type nicotinic acetylcholine receptors
Authors: Green Benedict T. , Lee Stephen T. , Panter Kip E. , Welch Kevin D. , Cook Daniel , Pfister James A. , Kem William R.
Published: June 2021

Piperidine alkaloids are found in many species of plants including Conium maculatum, Nicotiana spp., and Lupinus spp. A pharmacodynamic comparison was made of the alkaloids ammodendrine, anabasine, anabaseine, and coniine in; SH‐SY5Y cells which express autonomic‐type nicotinic acetylcholine receptors (nAChR), and in TE‐671 cells which express fetal muscle‐type nAChR. Both cell lines were cultured in DMEM supplemented with fetal bovine serum and penicillin/streptomycin. Membrane depolarization responses were measured by changes in fluorescence of a membrane potential‐sensitive dye. The alkaloids and their enantiomers were more effective in depolarizing TE‐671 cells relative to SH‐SY5Y cells. The rank order of potency in TE‐671 cells was: anabaseine > (+)‐anabasine > (−)‐anabasine > (±)‐anabasine > (−)‐coniine > (±)‐coniine > (+)‐coniine > (±)‐ammodendrine > (+)‐ammodendrine. The rank order potency in SH‐SY5Y cells was: anabaseine > (+)‐anabasine > (−)‐coniine > (+)‐coniine > (+)‐ammodendrine > (−)‐anabasine > (±)‐coniine > (±)‐anabasine > (−)‐ammodendrine. The actions of these alkaloids at nAChRs in both cell lines could be distinguished by their maximum effects in depolarizing cell membrane potential. It is possible that the mechanism behind the toxic potential of these compounds is the activation of muscle‐type nAChR followed by desensitization. Research supported by ARS‐USDA.
Effects of nicotine pretreatment on cocaine‐seeking behavior
Authors: Mojica Celina Yvonne , Belluzzi James D. , Leslie Frances M
Published: June 2021

Adolescence is a period marked by increased engagement in risky behaviors, such as the initiation of drug use. Adolescents tend to start by using tobacco and later progress to illicit drugs, such as cocaine. This has led to the hypothesis that nicotine, the main psychoactive component of tobacco smoke, is a ‘gateway’ drug that sensitizes the brain to other drugs of abuse. Our lab has previously shown data in support of this hypothesis, showing that a brief low‐dose nicotine treatment increases initial acquisition of cocaine self‐administration in adolescents. The purpose of the present study was to extend the analysis of the effects of nicotine pretreatment to extinction and reinstatement of cocaine‐seeking behavior. Male Sprague‐Dawley rats, aged postnatal day (P) 28 or P86, were given two daily intravenous injections of nicotine or saline for four consecutive days. At P32 or P90, rats self‐administered cocaine for 2 hr daily for at least 12 days. Animals then underwent extinction for a minimum of 7 days or until extinction requirements were met. Rats were reinstated either with a cocaine priming injection or reintroduction of drug‐associated cues. Initial data suggests there is a nicotine pretreatment effect on acquisition and extinction in adolescent rats. Adolescent rats pretreated with nicotine acquire cocaine self‐administration earlier and extinguish faster than adolescents pretreated with saline.
Exploration of novel radioiodine‐labeling techniques for opioid peptides
Authors: Pickett Julie E. , Majumdar Susruta , Burgman Maxim , Pasternak Gavril W.
Published: June 2021

A vast number of opioid peptides are derived from processing of precursors from three separate genes. The prodynorphin gene generates dynorphin A, the predominant product and the natural ligand for the kappa1 opioid receptor. However, other products of this gene have also been identified, including dynorphin B and α‐neoendorphin. Studies of kappa receptors have utilized 3H‐U69,593, a highly selective drug with poor affinity for both mu and delta opioid receptors. However, evidence suggests that 3H‐U69,593 may be labeling more than one class of kappa receptor in brain tissue. Further exploration of these binding sites requires the development of novel radioligands. In an effort to further the characterization of these potential kappa receptor subtypes, we have developed 125I‐labeled opioid peptides with high affinity and established receptor binding assays for them. Funded by grants to GWP (DA0641, DA07242, DA02615 and DA00220) and a training grant to JEP (DA07274) from the National Insitute on Drug Abuse.
Alpha‐1A Adrenergic Receptor Stimulation Enhances Learning & Memory in Mice
Authors: Goldenstein Brianna L , Lyons Mariaha , Wood Sarah , Nelson Brian , Fagerlie Ruby , Haselton James , Perez Dianne , Doze Van
Published: June 2021

Alzheimer's Disease impacts millions of people in the world today, resulting in decreased cognitive function with age. The noradrenergic system serves many functions in the brain, including mediating learning and memory through the production and distribution of norepinephrine (NE) throughout the brain. NE binds to three types of adrenergic receptors (ARs); α1, α2, and β, each containing three subtypes. The role of the noradrenergic system in regulating learning and memory was explored using transgenic mice created to overexpress the wild‐type (WT) receptor or a constitutively active mutant (CAM) α1AAR subtype. Recently, we showed that over‐expression/stimulation of the α1AAR in mice results in an increase in adult neurogenesis. During this investigation, we tested CAM α1AAR transgenic mice and normal mice to determine if there were any differences in their learning and/or memory. The results indicated a decrease in the amount of errors and total time to solve the Barnes Maze by the CAM α1AAR transgenic mice when compared to normal WT mice. This indicates that the α1AAR plays an important role in learning and memory, a finding which may impact our treatment of Alzheimer's Disease